Spirocyclic heterocyclic compounds useful as HIV integrase inhibitors

ABSTRACT

The present invention relates to Spirocyclic Heterocycle Compounds of Formula (I): and pharmaceutically acceptable salts thereof, wherein A, B, X, Y, R 1 , R 2  and R 4  are as defined herein. The present invention also relates to compositions comprising at least one Spirocyclic Heterocycle Compound, and methods of using the Spirocyclic Heterocycle Compounds for treating or preventing HIV infection in a subject.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a U.S. National Phase application under 35 U.S.C. §371 of PCT Application No. PCT/US2015/063850 filed Dec. 4, 2015, whichclaims priority from PCT Application No. PCT/CN14/093335 filed Dec. 9,2014.

FIELD OF THE INVENTION

The present invention relates to Spirocyclic Heterocycle Compounds,compositions comprising at least one Spirocyclic Heterocycle Compound,and methods of using the Spirocyclic Heterocycle Compounds for treatingor preventing HIV infection in a subject.

BACKGROUND OF THE INVENTION

A retrovirus designated human immunodeficiency virus (HIV), particularlythe strains known as HIV type-1 (HIV-1) virus and type-2 (HIV-2) virus,is the etiological agent of the complex disease that includesprogressive destruction of the immune system (acquired immune deficiencysyndrome; AIDS) and degeneration of the central and peripheral nervoussystem. A common feature of retrovirus replication is the insertion byvirally-encoded integrase of +proviral DNA into the host cell genome, arequired step in HIV replication in human T-lymphoid and monocytoidcells. Integration is believed to be mediated by integrase in threesteps: assembly of a stable nucleoprotein complex with viral DNAsequences; cleavage of two nucleotides from the 3′ termini of the linearproviral DNA; covalent joining of the recessed 3′ OH termini of theproviral DNA at a staggered cut made at the host target site. The fourthstep in the process, repair synthesis of the resultant gap, may beaccomplished by cellular enzymes.

Nucleotide sequencing of HIV shows the presence of a pol gene in oneopen reading frame [Ratner, L. et al., Nature, 313, 277(1985)]. Aminoacid sequence homology provides evidence that the pol sequence encodesreverse transcriptase, integrase and an HIV protease [Tohours, H. etal., EMBO J. 4, 1267 (1985); Power, M. D. et al., Science, 231, 1567(1986); Pearl, L. H. et al., Nature, 329, 351 (1987)]. All three enzymeshave been shown to be essential for the replication of HIV.

It is known that some antiviral compounds which act as inhibitors of HIVreplication are effective agents in the treatment of AIDS and similardiseases, including reverse transcriptase inhibitors such asazidothymidine (AZT) and efavirenz and protease inhibitors such asindinavir and nelfinavir. The compounds of this invention are inhibitorsof HIV integrase and inhibitors of HIV replication.

SUMMARY OF THE INVENTION

In one aspect, the present invention provides Compounds of Formula (I):

or a pharmaceutically acceptable salt thereof,wherein:

A is —NHC(O)— or 5- or 6-membered monocyclic heteroaryl;

B is a 3 to 8-membered heterocycloalkyl, which can be optionallysubstituted with one or more groups, each independently selected fromR⁵;

X is C₁-C₄ alkylene;

R¹ is selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl,C₁-C₆ hydroxyalkyl, —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄alkylene)-S—(C₁-C₆ alkyl), —(C₁-C₄ alkylene)-SO₂—(C₁-C₆ alkyl), —N(C₁-C₆alkyl)₂, —(C₁-C₄ alkylene)-N(C₁-C₆ alkyl)₂, —(C₁-C₄alkylene)-P(O)(OR⁸)₂, —(C₁-C₄ alkylene)-R⁹, phenyl, 3 to 8-memberedmonocyclic heterocycloalkyl and 5- or 6-membered monocyclic heteroaryl;

R² represents up to 3 optional substitutents, each independentlyselected from halo, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl) and C₁-C₆ haloalkyl;

each occurrence of R³ is independently selected from H, C₁-C₆ alkyl,—OH, —O—(C₁-C₆ alkyl), C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, —S—(C₁-C₆alkyl), —(C₁-C₄ alkylene)_(m)-P(O)(OR⁸)₂, —(C₁-C₄ alkylene)_(m)-R⁹,—NH₂, —NH(C₁-C₆ alkyl) and —N(C₁-C₆ alkyl)₂;

R⁴ is selected from C₁-C₆ alkyl, C₃-C₇ cycloalkyl, —(C₁-C₄alkylene)-O—(C₁-C₆ alkyl) and C₁-C₆ haloalkyl;

each occurrence of R⁵ is independently selected from halo, C₁-C₆ alkyl,C₁-C₆ haloalkyl, 3 to 8-membered monocyclic heterocycloalkyl, 6 to10-membered bicyclic heterocycloalkyl, —O—(C₁-C₆ alkyl), —O—(C₆-C₁₀aryl), —O—(C₁-C₆ alkylene)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl),—O—(C₁-C₆ alkylene)-O—(C₁-C₆ alkylene)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆alkyl), —N(C₁-C₆ alkyl)₂, —S(O)₂(C₁-C₆ alkyl), —NHS(O)₂—(C₁-C₆ alkyl),—S(O)₂NH—(C₁-C₆ alkyl), —OC(O)—(C₁-C₆haloalkyl), —(C₁-C₆alkylene)_(p)-C(O)O—(C₁-C₆ alkyl), —(C₁-C₆ alkylene)_(p)-C(O)—(C₁-C₆alkyl), —(C₁-C₆ alkylene)_(p)-C(O)N(R⁶)₂, C₁-C₆ hydroxyalkyl—(C₁-C₄alkylene)_(m)-P(O)(OR⁸)₂, —(C₁-C₄ alkylene)_(m)-R⁹ and —CN;

each occurrence of R⁶ is independently selected from H, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl and —(C₁-C₆ alkylene)_(p)—R⁷; eachoccurrence of R⁷ is independently selected from H, C₁-C₆ alkyl,—O—(C₁-C₆ alkyl), C₃-C₇ cycloalkyl, 5- or 6-membered monocyclicheteroaryl and 3 to 8-membered monocyclic heterocycloalkyl;

each occurrence of R⁸ is independently selected from H, C₁-C₆ alkyl and—(C₁-C₃ alkylene)-O(C)O—(C₁-C₆ alkyl);

each occurrence of R⁹ is independently :

each occurrence of R¹⁰ is independently selected from H, C₆-C₁₀ aryl, 5-or 6-membered monocyclic heteroaryl or 9- or 10-membered bicyclicheteroaryl;

each occurrence of R¹¹ is independently selected from H, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, phenyl or benzyl;

each occurrence of e is independently selected from H, C₁-C₆ alkyl,C₃-C₇ cycloalkyl, phenyl or benzyl;

each occurrence of R¹³ is independently C₁-C₆ alkyl;

each occurrence of m is independently 0 or 1.and

each occurrence of p is independently 0 or 1.

The Compounds of Formula (I) (also referred to herein as the“Spirocyclic Heterocycle Compounds”) and pharmaceutically acceptablesalts thereof, can be useful, for example, for inhibiting HIV viralreplication or replicon activity, and for treating or preventing

HIV infection in a subject. Without being bound by any specific theory,it is believed that the Spirocyclic Heterocycle Compounds inhibit HIVviral replication by inhibiting HIV Integrase.

Accordingly, the present invention provides methods for treating orpreventing HIV infection in a subject, comprising administering to thesubject an effective amount of at least one Spirocyclic HeterocycleCompound.

The details of the invention are set forth in the accompanying detaileddescription below.

Although any methods and materials similar to those described herein canbe used in the practice or testing of the present invention,illustrative methods and materials are now described. Other embodiments,aspects and features of the present invention are either furtherdescribed in or will be apparent from the ensuing description, examplesand appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The present invention includes to Spirocyclic Heterocycle Compounds,compositions comprising at least one Spirocyclic Heterocycle Compound,and methods of using the Spirocyclic Heterocycle Compounds for treatingor preventing HIV infection in a subject.

Definitions and Abbreviations

The terms used herein have their ordinary meaning and the meaning ofsuch terms is independent at each occurrence thereof. Thatnotwithstanding and except where stated otherwise, the followingdefinitions apply throughout the specification and claims. Chemicalnames, common names, and chemical structures may be used interchangeablyto describe the same structure. These definitions apply regardless ofwhether a term is used by itself or in combination with other terms,unless otherwise indicated. Hence, the definition of “alkyl” applies to“alkyl” as well as the “alkyl” portions of “hydroxyalkyl,” “haloalkyl,”“—O-alkyl,” etc. . . .

As used herein, and throughout this disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

A “subject” is a human or non-human mammal. In one embodiment, a subjectis a human. In another embodiment, a subject is a primate. In anotherembodiment, a subject is a monkey. In another embodiment, a subject is achimpanzee. In still another embodiment, a subject is a rhesus monkey.

The term “effective amount” as used herein, refers to an amount ofSpirocyclic Heterocycle Compound and/or an additional therapeutic agent,or a composition thereof that is effective in producing the desiredtherapeutic, ameliorative, inhibitory or preventative effect whenadministered to a subject suffering from HIV infection or AIDS. In thecombination therapies of the present invention, an effective amount canrefer to each individual agent or to the combination as a whole, whereinthe amounts of all agents administered are together effective, butwherein the component agent of the combination may not be presentindividually in an effective amount.

The term “preventing,” as used herein with respect to an HIV viralinfection or AIDS, refers to reducing the likelihood or severity of HIVinfection or AIDS.

The term “alkyl,” as used herein, refers to an aliphatic hydrocarbongroup having one of its hydrogen atoms replaced with a bond. An alkylgroup may be straight or branched and contain from about 1 to about 20carbon atoms. In one embodiment, an alkyl group contains from about 1 toabout 12 carbon atoms. In different embodiments, an alkyl group containsfrom 1 to 6 carbon atoms (C₁-C₆ alkyl) or from about 1 to about 4 carbonatoms (C₁-C₄ alkyl). Non-limiting examples of alkyl groups includemethyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl,tert-butyl, n-pentyl, neopentyl, isopentyl, n-hexyl, isohexyl andneohexyl. An alkyl group may be unsubstituted or substituted by one ormore substituents which may be the same or different, each substituentbeing independently selected from the group consisting of halo, alkenyl,alkynyl, aryl, cycloalkyl, cyano, hydroxy, —O-alkyl, —O-aryl,-alkylene-O-alkyl, alkylthio, —NH₂, —NH(alkyl), —N(alkyl)₂,—NH(cycloalkyl), —O—C(O)-alkyl, —O—C(O)-aryl, —O—C(O)-cycloalkyl,—C(O)OH and —C(O)O-alkyl. In one embodiment, an alkyl group is linear.In another embodiment, an alkyl group is branched. Unless otherwiseindicated, an alkyl group is unsubstituted.

The term “alkenyl,” as used herein, refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon double bond and having oneof its hydrogen atoms replaced with a bond. An alkenyl group may bestraight or branched and contain from about 2 to about 15 carbon atoms.In one embodiment, an alkenyl group contains from about 2 to about 12carbon atoms. In another embodiment, an alkenyl group contains fromabout 2 to about 6 carbon atoms. Non-limiting examples of alkenyl groupsinclude ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl,octenyl and decenyl. An alkenyl group may be unsubstituted orsubstituted by one or more substituents which may be the same ordifferent, each substituent being independently selected from the groupconsisting of halo, alkenyl, alkynyl, aryl, cycloalkyl, cyano, hydroxy,—O-alkyl, —O-aryl, -alkylene-O-alkyl, alkylthio, —NH₂, —NH(alkyl),—N(alkyl)₂, —NH(cycloalkyl), —O—C(O)-alkyl, —O—C(O)-aryl,—O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. The term “C₂-C₆ alkenyl”refers to an alkenyl group having from 2 to 6 carbon atoms. Unlessotherwise indicated, an alkenyl group is unsubstituted.

The term “alkynyl,” as used herein, refers to an aliphatic hydrocarbongroup containing at least one carbon-carbon triple bond and having oneof its hydrogen atoms replaced with a bond. An alkynyl group may bestraight or branched and contain from about 2 to about 15 carbon atoms.In one embodiment, an alkynyl group contains from about 2 to about 12carbon atoms. In another embodiment, an alkynyl group contains fromabout 2 to about 6 carbon atoms. Non-limiting examples of alkynyl groupsinclude ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. An alkynylgroup may be unsubstituted or substituted by one or more substituentswhich may be the same or different, each substituent being independentlyselected from the group consisting of halo, alkenyl, alkynyl, aryl,cycloalkyl, cyano, hydroxy, —O-alkyl, —O-aryl, -alkylene-O-alkyl,alkylthio, —NH₂, —NH(alkyl), —N(alkyl)₂, —NH(cycloalkyl), —O—C(O)-alkyl,—O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(O)OH and —C(O)O-alkyl. The term“C₂-C₆ alkynyl” refers to an alkynyl group having from 2 to 6 carbonatoms. Unless otherwise indicated, an alkynyl group is unsubstituted.

The term “alkylene,” as used herein, refers to an alkyl group, asdefined above, wherein one of the alkyl group's hydrogen atoms has beenreplaced with a bond. Non-limiting examples of alkylene groups include—CH₂—, —CH₂CH₂—, —CH₂CH₂CH₂—, —CH₂CH₂CH₂CH₂—, —CH(CH₃)CH₂CH₂—, —CH(CH₃)—and —CH₂CH(CH₃)CH₂—. In one embodiment, an alkylene group has from 1 toabout 6 carbon atoms. In another embodiment, an alkylene group has fromabout 3 to about 5 carbon atoms. In another embodiment, an alkylenegroup is branched. In another embodiment, an alkylene group is linear.In one embodiment, an alkylene group is —CH₂—. The term “C₁-C₄ alkylene”refers to an alkylene group having from 1 to 4 carbon atoms. The term“C₁-C₆ alkylene” refers to an alkylene group having from 1 to 6 carbonatoms.

The term “alkenylene,” as used herein, refers to an alkenyl group, asdefined above, wherein one of the alkenyl group's hydrogen atoms hasbeen replaced with a bond. Non-limiting examples of alkenylene groupsinclude —CH═CH—, —CH═CHCH₂—, —CH₂CH═CH—, —CH₂CH═CHCH₂—, —CH═CHCH₂CH₂—,—CH₂CH₂CH═CH— and —CH(CH₃)CH═CH—. In one embodiment, an alkenylene grouphas from 2 to about 6 carbon atoms. In another embodiment, an alkenylenegroup has from about 3 to about 5 carbon atoms. In another embodiment,an alkenylene group is branched. In another embodiment, an alkenylenegroup is linear. The term “C₂-C₆ alkylene” refers to an alkenylene grouphaving from 2 to 6 carbon atoms. The term “C₃-C₅ alkenylene” refers toan alkenylene group having from 3 to 5 carbon atoms.

The term “aryl,” as used herein, refers to an aromatic monocyclic ormulticyclic ring system comprising from about 6 to about 14 carbonatoms. In one embodiment, an aryl group contains from about 6 to about10 carbon atoms. An aryl group can be optionally substituted with one ormore “ring system substituents” which may be the same or different, andare as defined herein below. In one embodiment, an aryl group can beoptionally fused to a cycloalkyl or cycloalkanoyl group. Non-limitingexamples of aryl groups include phenyl and naphthyl. In one embodiment,an aryl group is phenyl. Unless otherwise indicated, an aryl group isunsubstituted.

The term “arylene,” as used herein, refers to a bivalent group derivedfrom an aryl group, as defined above, by removal of a hydrogen atom froma ring carbon of an aryl group. An arylene group can be derived from amonocyclic or multicyclic ring system comprising from about 6 to about14 carbon atoms. In one embodiment, an arylene group contains from about6 to about 10 carbon atoms. In another embodiment, an arylene group is anaphthylene group. In another embodiment, an arylene group is aphenylene group. An arylene group can be optionally substituted with oneor more “ring system substituents” which may be the same or different,and are as defined herein below. An arylene group is divalent and eitheravailable bond on an arylene group can connect to either group flankingthe arylene group. For example, the group “A-arylene-B,” wherein thearylene group is:

is understood to represent both:

In one embodiment, an arylene group can be optionally fused to acycloalkyl or cycloalkanoyl group. Non-limiting examples of arylenegroups include phenylene and naphthalene. In one embodiment, an arylenegroup is unsubstituted. In another embodiment, an arylene group is:

Unless otherwise indicated, an arylene group is unsubstituted.

The term “cycloalkyl,” as used herein, refers to a non-aromatic mono- ormulticyclic ring system comprising from about 3 to about 10 ring carbonatoms. In one embodiment, a cycloalkyl contains from about 5 to about 10ring carbon atoms. In another embodiment, a cycloalkyl contains fromabout 3 to about 7 ring atoms. In another embodiment, a cycloalkylcontains from about 5 to about 6 ring atoms. The term “cycloalkyl” alsoencompasses a cycloalkyl group, as defined above, which is fused to anaryl (e.g., benzene) or heteroaryl ring. Non-limiting examples ofmonocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl and cyclooctyl. Non-limiting examples ofmulticyclic cycloalkyls include 1-decalinyl, norbornyl and adamantyl. Acycloalkyl group can be optionally substituted with one or more “ringsystem substituents” which may be the same or different, and are asdefined herein below. In one embodiment, a cycloalkyl group isunsubstituted. The term “3 to 7-membered cycloalkyl” refers to acycloalkyl group having from 3 to 7 ring carbon atoms. Unless otherwiseindicated, a cycloalkyl group is unsubstituted. A ring carbon atom of acycloalkyl group may be functionalized as a carbonyl group. Anillustrative example of such a cycloalkyl group (also referred to hereinas a “cycloalkanoyl” group) includes, but is not limited to,cyclobutanoyl:

The term “halo,” as used herein, means —F, —Cl, —Br or —I.

The term “haloalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshas been replaced with a halogen. In one embodiment, a haloalkyl grouphas from 1 to 6 carbon atoms. In another embodiment, a haloalkyl groupis substituted with from 1 to 3 F atoms. Non-limiting examples ofhaloalkyl groups include —CH₂F, —CHF₂, —CF₃, —CH₂C1 and —CCl₃. The term“C₁-C₆ haloalkyl” refers to a haloalkyl group having from 1 to 6 carbonatoms.

The term “hydroxyalkyl,” as used herein, refers to an alkyl group asdefined above, wherein one or more of the alkyl group's hydrogen atomshave been replaced with an —OH group. In one embodiment, a hydroxyalkylgroup has from 1 to 6 carbon atoms. Non-limiting examples ofhydroxyalkyl groups include —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH and—CH₂CH(OH)CH₃. The term “C₁-C₆ hydroxyalkyl” refers to a hydroxyalkylgroup having from 1 to 6 carbon atoms.

The term “heteroaryl,” as used herein, refers to an aromatic monocyclicor multicyclic ring system comprising about 5 to about 14 ring atoms,wherein from 1 to 4 of the ring atoms is independently O, N or S and theremaining ring atoms are carbon atoms. In one embodiment, a heteroarylgroup has 5 to 10 ring atoms. In another embodiment, a heteroaryl groupis monocyclic and has 5 or 6 ring atoms. In another embodiment, aheteroaryl group is bicyclic. A heteroaryl group can be optionallysubstituted by one or more “ring system substituents” which may be thesame or different, and are as defined herein below. A heteroaryl groupis joined via a ring carbon atom, and any nitrogen atom of a heteroarylcan be optionally oxidized to the corresponding N-oxide. The term“heteroaryl” also encompasses a heteroaryl group, as defined above,which is fused to a benzene ring. Non-limiting examples of heteroarylsinclude pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone(including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl,oxadiazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, triazolyl,1,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl,oxindolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl,benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl,quinolinyl, imidazolyl, benzimidazolyl, thienopyridyl, quinazolinyl,thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl,benzoazaindolyl, 1,2,4-triazinyl, benzothiazolyl and the like, and allisomeric forms thereof The term “heteroaryl” also refers to partiallysaturated heteroaryl moieties such as, for example,tetrahydroisoquinolyl, tetrahydroquinolyl and the like. In oneembodiment, a heteroaryl group is a 5-membered heteroaryl. In anotherembodiment, a heteroaryl group is a 6-membered monocyclic heteroaryl. Inanother embodiment, a heteroaryl group comprises a 5- to 6-memberedmonocyclic heteroaryl group fused to a benzene ring. Unless otherwiseindicated, a heteroaryl group is unsubstituted.

The term “heterocycloalkyl,” as used herein, refers to a non-aromaticsaturated monocyclic or multicyclic ring system comprising 3 to about 11ring atoms, wherein from 1 to 4 of the ring atoms are independently O,S, N or Si, and the remainder of the ring atoms are carbon atoms. Aheterocycloalkyl group can be joined via a ring carbon, ring siliconatom or ring nitrogen atom. In one embodiment, a heterocycloalkyl groupis monocyclic and has from about 3 to about 7 ring atoms. In oneembodiment, a heterocycloalkyl group is monocyclic and has from about 3to about 8 ring atoms. In another embodiment, a heterocycloalkyl groupis monocyclic has from about 4 to about 7 ring atoms. In anotherembodiment, a heterocycloalkyl group is bicyclic and has from about 7 toabout 11 ring atoms. In still another embodiment, a heterocycloalkylgroup is monocyclic and has 5 or 6 ring atoms. In one embodiment, aheterocycloalkyl group is monocyclic. In another embodiment, aheterocycloalkyl group is bicyclic. There are no adjacent oxygen and/orsulfur atoms present in the ring system. Any —NH group in aheterocycloalkyl ring may exist protected such as, for example, as an—N(BOC), —N(Cbz), —N(Tos) group and the like; such protectedheterocycloalkyl groups are considered part of this invention. The term“heterocycloalkyl” also encompasses a heterocycloalkyl group, as definedabove, which is fused to an aryl (e.g., benzene) or heteroaryl ring. Aheterocycloalkyl group can be optionally substituted by one or more“ring system substituents” which may be the same or different, and areas defined herein below. The nitrogen or sulfur atom of theheterocycloalkyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of monocyclicheterocycloalkyl rings include oxetanyl, piperidyl, pyrrolidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydrothiophenyl, delta-lactam, delta-lactone andthe like, and all isomers thereof.

A ring carbon atom of a heterocycloalkyl group may be functionalized asa carbonyl group. An illustrative example of such a heterocycloalkylgroup is:

In one embodiment, a heterocycloalkyl group is a 5-membered monocyclicheterocycloalkyl. In another embodiment, a heterocycloalkyl group is a6-membered monocyclic heterocycloalkyl. The term “3 to 6-memberedmonocyclic heterocycloalkyl” refers to a monocyclic heterocycloalkylgroup having from 3 to 6 ring atoms. The term “3 to 8-memberedmonocyclic heterocycloalkyl” refers to a monocyclic heterocycloalkylgroup having from 3 to 8 ring atoms. The term “4 to 7-memberedmonocyclic heterocycloalkyl” refers to a monocyclic heterocycloalkylgroup having from 4 to 7 ring atoms. The term “7 to 11-membered bicyclicheterocycloalkyl” refers to a bicyclic heterocycloalkyl group havingfrom 7 to 11 ring atoms. Unless otherwise indicated, a heterocycloalkylgroup is unsubstituted.

Examples of “ring system substituents,” include, but are not limited to,alkyl, alkenyl, alkynyl, aryl, heteroaryl, -alkylene-aryl,-arylene-alkyl, -alkylene-heteroaryl, -alkenylene-heteroaryl,-alkynylene-heteroaryl, —OH, hydroxyalkyl, haloalkyl, —O-alkyl,—O-haloalkyl, -alkylene-O-alkyl, —O-aryl, —O-alkylene-aryl, acyl,—C(O)-aryl, halo, —NO₂, —CN, —SF₅, —C(O)OH, —C(O)O-alkyl, —C(O)O-aryl,—C(O)O-alkylene-aryl, —S(O)-alkyl, —S(O)₂-alkyl, —S(O)-aryl,—S(O)₂-aryl, —S(O)-heteroaryl, —S(O)₂-heteroaryl, —S-alkyl, —S-aryl,—S-heteroaryl, —S-alkylene-aryl, —S-alkylene-heteroaryl,—S(O)₂-alkylene-aryl, —S(O)₂-alkylene-heteroaryl, —Si(alkyl)₂,—Si(aryl)₂, —Si(heteroaryl)₂, —Si(alkyl)(aryl), —Si(alkyl)(cycloalkyl),—Si(alkyl)(heteroaryl), cycloalkyl, heterocycloalkyl, —O—C(O)-alkyl,—O—C(O)-aryl, —O—C(O)-cycloalkyl, —C(═N—CN)—NH₂, —C(═NH)—NH₂,—C(═NH)—NH(alkyl), —N(Y₁)(Y₂), -alkylene-N(Y₁)(Y₂), —C(O)N(Y₁)(Y₂) and—S(O)₂N(Y₁)(Y₂), wherein Y₁ and Y₂ can be the same or different and areindependently selected from the group consisting of hydrogen, alkyl,aryl, cycloalkyl, and -alkylene-aryl. “Ring system substituent” may alsomean a single moiety which simultaneously replaces two availablehydrogens on two adjacent carbon atoms (one H on each carbon) on a ringsystem. Examples of such moiety are methylenedioxy, ethylenedioxy,—C(CH₃)₂— and the like which form moieties such as, for example:

The term “substituted” means that one or more hydrogens on thedesignated atom is replaced with a selection from the indicated group,provided that the designated atom's normal valency under the existingcircumstances is not exceeded, and that the substitution results in astable compound. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds. By“stable compound' or “stable structure” is meant a compound that issufficiently robust to survive isolation to a useful degree of purityfrom a reaction mixture, and formulation into an efficacious therapeuticagent.

The term “in substantially purified form,” as used herein, refers to thephysical state of a compound after the compound is isolated from asynthetic process (e.g., from a reaction mixture), a natural source, ora combination thereof. The term “in substantially purified form,” alsorefers to the physical state of a compound after the compound isobtained from a purification process or processes described herein orwell-known to the skilled artisan (e.g., chromatography,recrystallization and the like), in sufficient purity to becharacterizable by standard analytical techniques described herein orwell-known to the skilled artisan.

It should also be noted that any carbon as well as heteroatom withunsatisfied valences in the text, schemes, examples and tables herein isassumed to have the sufficient number of hydrogen atom(s) to satisfy thevalences.

When a functional group in a compound is termed “protected”, this meansthat the group is in modified form to preclude undesired side reactionsat the protected site when the compound is subjected to a reaction.Suitable protecting groups will be recognized by those with ordinaryskill in the art as well as by reference to standard textbooks such as,for example, T. W. Greene et al, Protective Groups in Organic Synthesis(1991), Wiley, New York.

When any substituent or variable (e.g., alkyl, R¹, R⁷, etc.) occurs morethan one time in any constituent or in Formula (I), its definition oneach occurrence is independent of its definition at every otheroccurrence, unless otherwise indicated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, from combination of the specifiedingredients in the specified amounts.

Prodrugs and solvates of the compounds of the invention are alsocontemplated herein. A discussion of prodrugs is provided in T. Higuchiand V. Stella, Pro-drugs as Novel Delivery Systems (1987) 14 of theA.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design,(1987) Edward B. Roche, ed., American Pharmaceutical Association andPergamon Press. The term “prodrug” means a compound (e.g., a drugprecursor) that is transformed in vivo to provide a SpirocyclicHeterocycle Compound or a pharmaceutically acceptable salt of thecompound. The transformation may occur by various mechanisms (e.g., bymetabolic or chemical processes), such as, for example, throughhydrolysis in blood. For example, if a Spirocyclic Heterocycle Compoundor a pharmaceutically acceptable salt, hydrate or solvate of thecompound contains a carboxylic acid functional group, a prodrug cancomprise an ester formed by the replacement of the hydrogen atom of theacid group with a group such as, for example, (C₁—C₈)alkyl,(C₂-C₁₂)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbonatoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms,1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms,1-methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms,N-(alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms,1-(N-(alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms,3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl,di-N,N-(C₁-C₂)alkylamino(C₂-C₃)alkyl (such as β-dimethylaminoethyl),carbamoyl-(C₁-C₂)alkyl, N,N-di(C₁-C₂)alkylcarbamoyl-(C₁-C₂)alkyl andpiperidino-, pyrrolidino- or morpholino(C₂-C₃)alkyl, and the like.

Similarly, if a Spirocyclic Heterocycle Compound contains an alcoholfunctional group, a prodrug can be formed by the replacement of one ormore of the hydrogen atoms of the alcohol groups with a group such as,for example, (C₁-C₆)alkanoyloxymethyl, 1-((C₁-C₆)alkanoyloxy)ethyl,1-methyl-1((C₁-C₆)alkanoyloxy)ethyl, (C₁-C₆)alkoxycarbonyloxymethyl,N-(C₁-C₆)alkoxycarbonylaminomethyl, succinoyl, (C₁-C₆)alkanoyl,α-amino(C₁-C₄)alkyl, α-amino(C₁-C₄)alkylene-aryl, arylacyl anda-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group isindependently selected from the naturally occurring L-amino acids, orglycosyl (the radical resulting from the removal of a hydroxyl group ofthe hemiacetal form of a carbohydrate).

If a Spirocyclic Heterocycle Compound incorporates an amine functionalgroup, a prodrug can be formed by the replacement of a hydrogen atom inthe amine group with a group such as, for example, R-carbonyl-,RO-carbonyl-, NRR′-carbonyl- wherein R and R′ are each independently(C₁-C₁₀)alkyl, (C₃-C₇) cycloalkyl, benzyl, a natural α-aminoacyl,—C(OH)C(O)OY¹ wherein Y¹ is H, (C₁-C₆)alkyl or benzyl, —C(OY²)Y³ whereinY² is (C₁-C₄) alkyl and Y³ is (C₁-C₆)alkyl; carboxy (C₁-C₆)alkyl;amino(C₁-C₄)alkyl or mono-N— or di-N,N-(C₁-C₆)alkylaminoalkyl; —C(Y⁴)Y⁵wherein Y⁴ is H or methyl and Y⁵ is mono-N— or di-N,N—(C₁-C₆)alkylaminomorpholino; piperidin-1-yl or pyrrolidin-1-yl, and the like.

Pharmaceutically acceptable esters of the present compounds include thefollowing groups: (1) carboxylic acid esters obtained by esterificationof the hydroxy group of a hydroxyl compound, in which the non-carbonylmoiety of the carboxylic acid portion of the ester grouping is selectedfrom straight or branched chain alkyl (e.g., methyl, ethyl, n-propyl,isopropyl, t-butyl, sec-butyl or n-butyl), alkoxyalkyl (e.g.,methoxymethyl), aralkyl (e.g., benzyl), aryloxyalkyl (for example,phenoxymethyl), aryl (e.g., phenyl optionally substituted withours, forexample, halogen, C₁₋₄alkyl, —O—(C₁₋₄alkyl) or amino); (2) sulfonateesters, such as alkyl- or aralkylsulfonyl (for example,methanesulfonyl); (3) amino acid esters, including those correspondingto both natural and non-natural amino acids (e.g., L-valyl orL-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphateesters. The phosphate esters may be further esterified by, for example,a C₁₋₂₀ alcohol or reactive derivative thereof, or by a2,3-di(C₆₋₂₄)acyl glycerol. One or more compounds of the invention mayexist in unsolvated as well as solvated forms with pharmaceuticallyacceptable solvents such as water, ethanol, and the like, and it isintended that the invention embrace both solvated and unsolvated forms.“Solvate” means a physical association of a compound of this inventionwith one or more solvent molecules. This physical association involvesvarying degrees of ionic and covalent bonding, including hydrogenbonding. In certain instances the solvate will be capable of isolation,for example when one or more solvent molecules are incorporated in thecrystal lattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolatable solvates. Non-limiting examples ofsolvates include ethanolates, methanolates, and the like. A “hydrate” isa solvate wherein the solvent molecule is water.

One or more compounds of the invention may optionally be converted to asolvate. Preparation of solvates is generally known. Thus, for example,M. Caira et al, J. Pharmaceutical Sci., 93(3), 601-611 (2004) describethe preparation of the solvates of the antifungal fluconazole in ethylacetate as well as from water. Similar preparations of solvates,hemisolvate, hydrates and the like are described by E. C. van Tonder etal, AAPS PharmSciTechours. , 5(1), article 12 (2004); and A. L. Binghamet al, Chem. Commun., 603-604 (2001). A typical, non-limiting, processinvolves dissolving the inventive compound in desired amounts of thedesired solvent (organic or water or mixtures thereof) at a higher thanroom temperature, and cooling the solution at a rate sufficient to formcrystals which are then isolated by standard methods. Analyticaltechniques such as, for example IR spectroscopy, show the presence ofthe solvent (or water) in the crystals as a solvate (or hydrate).

The Spirocyclic Heterocycle Compounds can form salts which are alsowithin the scope of this invention. Reference to a SpirocyclicHeterocycle Compound herein is understood to include reference to saltsthereof, unless otherwise indicated. The term “salt(s)”, as employedherein, denotes acidic salts formed with inorganic and/or organic acids,as well as basic salts formed with inorganic and/or organic bases. Inaddition, when a Spirocyclic Heterocycle Compound contains both a basicmoiety, such as, but not limited to a pyridine or imidazole, and anacidic moiety, such as, but not limited to a carboxylic acid,zwitterions (“inner salts”) may be formed and are included within theterm “salt(s)” as used herein. In one embodiment, the salt is apharmaceutically acceptable (i.e., non-toxic, physiologicallyacceptable) salt. In another embodiment, the salt is other than apharmaceutically acceptable salt. Salts of the Compounds of Formula (I)may be formed, for example, by reacting a Spirocyclic HeterocycleCompound with an amount of acid or base, such as an equivalent amount,in a medium such as one in which the salt precipitates or in an aqueousmedium followed by lyophilization.

Exemplary acid addition salts include acetates, ascorbates, benzoates,benzenesulfonates, bisulfates, borates, butyrates, citrates,camphorates, camphorsulfonates, fumarates, hydrochlorides,hydrobromides, hydroiodides, lactates, maleates, methanesulfonates,naphthalenesulfonates, nitrates, oxalates, phosphates, propionates,salicylates, succinates, sulfates, tartarates, thiocyanates,toluenesulfonates (also known as tosylates) and the like.

Additionally, acids which are generally considered suitable for theformation of pharmaceutically useful salts from basic pharmaceuticalcompounds are discussed, for example, by P. Stahl et al, Camille G.(eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use.(2002) Zurich: Wiley-VCH; S. Berge et al, Journal of PharmaceuticalSciences (1977) 66(1) 1-19; P. Gould, International J. of Pharmaceutics(1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry(1996), Academic Press, New York; and in The Orange Book (Food & DrugAdministration, Washington, D.C. on their website). These disclosuresare incorporated herein by reference thereto.

Exemplary basic salts include ammonium salts, alkali metal salts such assodium, lithium, and potassium salts, alkaline earth metal salts such ascalcium and magnesium salts, salts with organic bases (for example,organic amines) such as dicyclohexylamine, t-butyl amine, choline, andsalts with amino acids such as arginine, lysine and the like. Basicnitrogen-containing groups may be quarternized with agents such as loweralkyl halides (e.g., methyl, ethyl, and butyl chlorides, bromides andiodides), dialkyl sulfates (e.g., dimethyl, diethyl, and dibutylsulfates), long chain halides (e.g., decyl, lauryl, and stearylchlorides, bromides and iodides), aralkyl halides (e.g., benzyl andphenethyl bromides), and others.

All such acid salts and base salts are intended to be pharmaceuticallyacceptable salts within the scope of the invention and all acid and basesalts are considered equivalent to the free forms of the correspondingcompounds for purposes of the invention.

Diastereomeric mixtures can be separated into their individualdiastereomers on the basis of their physical chemical differences bymethods well-known to those skilled in the art, such as, for example, bychromatography and/or fractional crystallization. Enantiomers can beseparated by converting the enantiomeric mixture into a diastereomericmixture by reaction with an appropriate optically active compound (e.g.,chiral auxiliary such as a chiral alcohol or

Mosher's acid chloride), separating the diastereomers and converting(e.g., hydrolyzing) the individual diastereomers to the correspondingpure enantiomers. Sterochemically pure compounds may also be prepared byusing chiral starting materials or by employing salt resolutiontechniques. Also, some of the Spirocyclic Heterocycle Compounds may beatropisomers (e.g., substituted biaryls) and are considered as part ofthis invention. Enantiomers can also be directly separated using chiralchromatographic techniques.

It is also possible that the Spirocyclic Heterocycle Compounds may existin different tautomeric forms, and all such forms are embraced withinthe scope of the invention. For example, all keto-enol and imine-enamineforms of the compounds are included in the invention.

All stereoisomers (for example, geometric isomers, optical isomers andthe like) of the present compounds (including those of the salts,solvates, hydrates, esters and prodrugs of the compounds as well as thesalts, solvates and esters of the prodrugs), such as those which mayexist due to asymmetric carbons on various substituents, includingenantiomeric forms (which may exist even in the absence of asymmetriccarbons), rotameric forms, atropisomers, and diastereomeric forms, arecontemplated within the scope of this invention. If a SpirocyclicHeterocycle Compound incorporates a double bond or a fused ring, boththe cis- and trans-forms, as well as mixtures, are embraced within thescope of the invention.

Individual stereoisomers of the compounds of the invention may, forexample, be substantially free of other isomers, or may be admixed, forexample, as racemates or with all other, or other selected,stereoisomers. The chiral centers of the present invention can have theS or R configuration as defined by the IUPAC 1974 Recommendations. Theuse of the terms “salt”, “solvate”, “ester”, “prodrug” and the like, isintended to apply equally to the salt, solvate, ester and prodrug ofenantiomers, stereoisomers, rotamers, tautomers, racemates or prodrugsof the inventive compounds.

In the Compounds of Formula (I), the atoms may exhibit their naturalisotopic abundances, or one or more of the atoms may be artificiallyenriched in a particular isotope having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of generic Formula I.For example, different isotopic forms of hydrogen (H) include protium(¹H) and deuterium (²H). Protium is the predominant hydrogen isotopefound in nature. Enriching for deuterium may provide certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched Compoundsof Formula (I) can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the Schemes and Examplesherein using appropriate isotopically-enriched reagents and/orintermediates. In one embodiment, a Compound of Formula (I) has one ormore of its hydrogen atoms replaced with deuterium.

The Spirocyclic Heterocycle Compounds are useful in human and veterinarymedicine for treating or preventing HIV infection in a subject. In oneembodiment, the Spirocyclic Heterocycle Compounds can be inhibitors ofHIV viral replication. In a specific embodiment, the SpirocyclicHeterocycle Compounds are inhibitors of HIV-1. Accordingly, theSpirocyclic Heterocycle Compounds are useful for treating HIV infectionsand AIDS. In accordance with the invention, the Spirocyclic HeterocycleCompounds can be administered to a subject in need of treatment orprevention of HIV infection.

Accordingly, in one embodiment, the invention provides methods fortreating HIV infection in a subject comprising administering to thesubject an effective amount of at least one Spirocyclic HeterocycleCompound or a pharmaceutically acceptable salt thereof. In a specificembodiment, the present invention provides methods for treating AIDS ina subject comprising administering to the subject an effective amount ofat least one Spirocyclic Heterocycle Compound or a pharmaceuticallyacceptable salt thereof.

The following abbreviations are used below and have the followingmeanings: Ac is acetyl or —C(O)CH₃, Bu is butyl; Boc₂O is di-tert-butyldicarbonate, DCM is dichloromethane, Dess-Martin Periodinane is1,1,1-triacetoxy-1,1-dihydro-1,2-benziodoxol-3(1H)-one, DIAD isdiisopropyl azodicarboxylate, DIPEA is N,N-diisopropylethylamine, DMF isN,N-dimethylformamide, EtOAc is ethyl acetate, EtOH is ethanol, HATU is1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate,N-[(Dimethylamino)-1H-1,2,3-triazolo-[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminiumhexafluorophosphate N-oxide, HPLC is high-pressure liquidchromatography, LCMS is liquid chromatography-mass spectrometry, LiHMDSis lithum hexamethyldisilazane, MeOH is methanol, NBS isN-bromosuccinimide, NHS is normal human serum, NMR is nuclear magneticresonance spectroscopy, Pd/C is palladium on carbon, Pd(Ph₃P)₄ istetrakis (triphenylphosphine) palladium(0), PyClu is1-(chloro-1-pyrrolidinylmethylene)pyrrolidinium hexafluorophosphate,PySO₃ is sulfur trioxide-pyridine complex, TLC is thin-layerchromatography and THF is tetrahydrofuran.

The Compounds of Formula (I)

The present invention provides Spirocyclic Heterocycle Compounds ofFormula

and pharmaceutically acceptable salts thereof, wherein A, B, X, R¹, R²,R³ and R⁴ are defined above for the Compounds of Formula (I).

In one embodiment, X is —CH₂—.

In another embodiment, X is —CH(CH₃)—.

In one embodiment, the compounds of formula (I) have the formula (Ia):

or a pharmaceutically acceptable salt thereof,wherein:

A is: —NHC(O)— or thiadiazolyl;

B is 4 to 7-membered monocyclic heterocycloalkyl;

R¹ is selected from C₁-C₆ alkyl, —N(C₁-C₆ alkyl)₂, C₁-C₆ hydroxyalkyland —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl);

R² represents up to 2 optional substituents, each independently selectedfrom halo; and

each occurrence of R³ is independently H or C₁-C₆ alkoxy.

In one embodiment, for the compounds of formula (I) or (Ia), A is—NHC(O)—.

In another embodiment, for the compounds of formula (I) or (Ia), A is 5-or 6-membered monocyclic heterocycloalkyl.

In another embodiment, for the compounds of formula (I) or (Ia), A is a5-membered monocyclic heterocycloalkyl.

In yet another embodiment, for the compounds of formula (I) or (Ia), Ais thiadiazolyl.

In another embodiment, for the compounds of formula (I) or (Ia), A is:

In one embodiment, for the compounds of formula (I) or (Ia), B is a4-membered monocyclic heterocycloalkyl group.

In another embodiment, for the compounds of formula (I) or (Ia), B is a5-membered monocyclic heterocycloalkyl group.

In another embodiment, for the compounds of formula (I) or (Ia), B is a6-membered monocyclic heterocycloalkyl group.

In one embodiment, for the compounds of formula (I) or (Ia), B isselected from:

In one embodiment, for the compounds of formula (I) or (Ia), R¹ is C₁-C₆alkyl.

In another embodiment, for the compounds of formula (I) or (Ia), R¹ is—(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl).

In another embodiment, for the compounds of formula (I) or (Ia), R¹ is—N(C₁-C₆ alkyl)₂.

In another embodiment, for the compounds of formula (I) or (Ia), R¹ isselected from methyl, ethyl, —N(CH₃)₂, —CH₂OCH₃, —CH₂CH₂OCH₃,—CH₂CH₂CH₂OCH₃ and —CH₂CH₂OCH₂CH₃.

In one embodiment, for the compounds of formula (I) or (Ia), eachoccurrence of R² is halo.

In another embodiment, for the compounds of formula (I) or (Ia), R²represents up to 3 substituent groups, each independently selected fromF and Cl.

In another embodiment, for the compounds of formula (I) or (Ia), R²represents 2 fluoro groups.

In another embodiment, for the compounds of formula (I) or (Ia), R²represents 2 fluoro groups, consisting of one fluoro group in the orthoposition and the second fluoro group in the para position on the phenylring to which they are each attached.

In one embodiment, for the compounds of formula (I) or (Ia), R² and thephenyl group to which R² is attached is selected from:

In one embodiment, for the compounds of formula (I) or (Ia), at leastone occurrence of R³ is H.

In another embodiment, for the compounds of formula (I) or (Ia), eachoccurrence of R³ is H.

In another embodiment, for the compounds of formula (I) or (Ia), eachoccurrence of R³ is other than H.

In one embodiment, for the compounds of formula (I) or (Ia), oneoccurrence of R³ is H and the other occurrence of R³ is H or —O—(C₁-C₆alkyl).

In another embodiment, for the compounds of formula (I) or (Ia), oneoccurrence of R³ is H and the other occurrence of R³ is H or methoxy.

In another embodiment, for the compounds of formula (I) or (Ia), oneoccurrence of R³ is H and the other occurrence of R³ is —O—(C₁-C₆alkyl).

In still another embodiment, for the compounds of formula (I) or (Ia),one occurrence of R³ is H and the other occurrence of R³ is methoxy.

In one embodiment, for the compounds of formula (I) or (Ia), R¹ is C₁-C₆alkyl or —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl); one occurrence of R³ is H;and the other occurrence of R³ is H or —O—(C₁-C₆ alkyl).

In another embodiment, for the compounds of formula (I) or (Ia), R¹ isselected from methyl, ethyl, —N(CH₃)₂, —CH₂OCH₃, —CH₂CH₂OCH₃,—CH₂CH₂CH₂OCH₃ and —CH₂CH₂OCH₂CH₃; one occurrence of R³ is H; and theother occurrence of R³ is methoxy.

In one embodiment, for the compounds of formula (I) or (Ia), R¹ is C₁-C₆alkyl or —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl); R² represents up to 3substituent groups, each independently selected from F and Cl; oneoccurrence of R³ is H; and the other occurrence of R³ is H or —O—(C₁-C₆alkyl); A is —NHC(O)—; and B is selected from:

In another embodiment, for the compounds of formula (I) or (Ia), R¹ isselected from methyl, ethyl, —N(CH₃)₂, —CH₂OCH₃, —CH₂CH₂OCH₃,—CH₂CH₂CH₂OCH₃ and —CH₂CH₂OCH₂CH₃; one occurrence of R³ is H; and theother occurrence of R³ is methoxy; A is —NHC(O)—; and B is selectedfrom:

In one embodiment, variables A, B, X, R¹, R², R³ and R⁴ for theCompounds of Formula (I) are selected independently of each other.

In another embodiment, the Compounds of Formula (I) are in substantiallypurified form.

Other embodiments of the present invention include the following:

(a) A pharmaceutical composition comprising an effective amount of aCompound of Formula (I) or a pharmaceutically acceptable salt thereof,and a pharmaceutically acceptable carrier.

(b) The pharmaceutical composition of (a), further comprising a secondtherapeutic agent selected from the group consisting of HIV antiviralagents, immunomodulators, and anti-infective agents.

(c) The pharmaceutical composition of (b), wherein the HIV antiviralagent is an antiviral selected from the group consisting of HIV proteaseinhibitors, HIV integrase inhibitors, nucleoside reverse transcriptaseinhibitors, CCRS co-receptor antagonists and non-nucleosidereverse-transcriptase inhibitors.

(d) A pharmaceutical combination that is (i) a Compound of Formula (I)and (ii) a second therapeutic agent selected from the group consistingof HIV antiviral agents, immunomodulators, and anti-infective agents;wherein the Compound of Formula (I) and the second therapeutic agent areeach employed in an amount that renders the combination effective forinhibiting HIV replication, or for treating HIV infection and/orreducing the likelihood or severity of symptoms of HIV infection.

(e) The combination of (d), wherein the HIV antiviral agent is anantiviral selected from the group consisting of HIV protease inhibitors,HIV integrase inhibitors, nucleoside reverse transcriptase inhibitors,CCRS co-receptor antagonists and non-nucleoside reverse-transcriptaseinhibitors.

(f) A method of inhibiting HIV replication in a subject in need thereofwhich comprises administering to the subject an effective amount of aCompound of Formula (I).

(g) A method of treating HIV infection and/or reducing the likelihood orseverity of symptoms of HIV infection in a subject in need thereof whichcomprises administering to the subject an effective amount of a Compoundof Formula (I).

(h) The method of (g), wherein the Compound of Formula (I) isadministered in combination with an effective amount of at least onesecond therapeutic agent selected from the group consisting of HIVantiviral agents, immunomodulators, and anti-infective agents.

(i) The method of (h), wherein the HIV antiviral agent is an antiviralselected from the group consisting of HIV protease inhibitors, HIVintegrase inhibitors, nucleoside reverse transcriptase inhibitors, CCR5co-receptor antagonists and non-nucleoside reverse-transcriptaseinhibitors.

(j) A method of inhibiting HIV replication in a subject in need thereofwhich comprises administering to the subject the pharmaceuticalcomposition of (a), (b) or (c) or the combination of (d) or (e).

(k) A method of treating HIV infection and/or reducing the likelihood orseverity of symptoms of HIV infection in a subject in need thereof whichcomprises administering to the subject the pharmaceutical composition of(a), (b) or (c) or the combination of (d) or (e).

The present invention also includes a compound of the present inventionfor use (i) in, (ii) as a medicament for, or (iii) in the preparation ofa medicament for: (a) medicine, (b) inhibiting HIV replication or (c)treating HIV infection and/or reducing the likelihood or severity ofsymptoms of HIV infection. In these uses, the compounds of the presentinvention can optionally be employed in combination with one or moresecond therapeutic agents selected from HIV antiviral agents,anti-infective agents, and immunomodulators.

Additional embodiments of the invention include the pharmaceuticalcompositions, combinations and methods set forth in (a)-(k) above andthe uses set forth in the preceding paragraphours, wherein the compoundof the present invention employed therein is a compound of one of theembodiments, aspects, classes, sub-classes, or features of the compoundsdescribed above. In all of these embodiments, the compound mayoptionally be used in the form of a pharmaceutically acceptable salt orhydrate as appropriate. It is understood that references to compoundswould include the compound in its present form as well as in differentforms, such as polymorphs, solvates and hydrates, as applicable.

It is further to be understood that the embodiments of compositions andmethods provided as (a) through (k) above are understood to include allembodiments of the compounds, including such embodiments as result fromcombinations of embodiments. The Compounds of Formula (I) may bereferred to herein by chemical structure and/or by chemical name. In theinstance that both the structure and the name of a Compound of Formula(I) are provided and a discrepancy is found to exist between thechemical structure and the corresponding chemical name, it is understoodthat the chemical structure will predominate.

Non-limiting examples of the Compounds of Formula (I) include compounds1-58 as set forth in the table below, and pharmaceutically acceptablesalts thereof An embodiment of the invention includes a compoundselected from compounds 1-58.

Compound Number Structure 1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

45

46

47

48

49

50

51

52

53

54

55

56

57

58

Treatment or Prevention of HIV Infection

The Spirocyclic Heterocycle Compounds are useful in the inhibition ofHIV, the inhibition of HIV integrase, the treatment of HIV infectionand/or reduction of the likelihood or severity of symptoms of HIVinfection and the inhibition of HIV viral replication and/or HIV viralproduction in a cell-based system. For example, the SpirocyclicHeterocycle Compounds are useful in treating infection by HIV aftersuspected past exposure to HIV by such means as blood transfusion,exchange of body fluids, bites, accidental needle stick, or exposure tosubject blood during surgery or other medical procedures.

Accordingly, in one embodiment, the invention provides methods fortreating HIV infection in a subject, the methods comprisingadministering to the subject an effective amount of at least oneSpirocyclic Heterocycle Compound or a pharmaceutically acceptable saltthereof. In a specific embodiment, the amount administered is effectiveto treat or prevent infection by HIV in the subject. In another specificembodiment, the amount administered is effective to inhibit HIV viralreplication and/or viral production in the subject. In one embodiment,the HIV infection has progressed to AIDS.

The Spirocyclic Heterocycle Compounds are also useful in the preparationand execution of screening assays for antiviral compounds. For examplethe Spirocyclic Heterocycle Compounds are useful for identifyingresistant HIV cell lines harboring mutations, which are excellentscreening tools for more powerful antiviral compounds. Furthermore, theSpirocyclic Heterocycle Compounds are useful in establishing ordetermining the binding site of other antivirals to the HIV Integrase.

The compositions and combinations of the present invention can be usefulfor treating a subject suffering from infection related to any HIVgenotype.

Combination Therapy

In another embodiment, the present methods for treating or preventingHIV infection can further comprise the administration of one or moreadditional therapeutic agents which are not Spirocyclic HeterocycleCompounds.

In one embodiment, the additional therapeutic agent is an antiviralagent.

In another embodiment, the additional therapeutic agent is animmunomodulatory agent, such as an immunosuppressive agent.

Accordingly, in one embodiment, the present invention provides methodsfor treating a viral infection in a subject, the method comprisingadministering to the subject: (i) at least one Spirocyclic HeterocycleCompound (which may include two or more different SpirocyclicHeterocycle Compounds), or a pharmaceutically acceptable salt thereof,and (ii) at least one additional therapeutic agent that is other than aSpirocyclic Heterocycle Compound, wherein the amounts administered aretogether effective to treat or prevent a viral infection.

When administering a combination therapy of the invention to a subject,therapeutic agents in the combination, or a pharmaceutical compositionor compositions comprising therapeutic agents, may be administered inany order such as, for example, sequentially, concurrently, together,simultaneously and the like. The amounts of the various actives in suchcombination therapy may be different amounts (different dosage amounts)or same amounts (same dosage amounts). Thus, for non-limitingillustration purposes, a Spirocyclic Heterocycle Compound and anadditional therapeutic agent may be present in fixed amounts (dosageamounts) in a single dosage unit (e.g., a capsule, a tablet and thelike).

In one embodiment, the at least one Spirocyclic Heterocycle Compound isadministered during a time when the additional therapeutic agent(s)exert their prophylactic or therapeutic effect, or vice versa.

In another embodiment, the at least one Spirocyclic Heterocycle Compoundand the additional therapeutic agent(s) are administered in dosescommonly employed when such agents are used as monotherapy for treatinga viral infection.

In another embodiment, the at least one Spirocyclic Heterocycle Compoundand the additional therapeutic agent(s) are administered in doses lowerthan the doses commonly employed when such agents are used asmonotherapy for treating a viral infection.

In still another embodiment, the at least one Spirocyclic HeterocycleCompound and the additional therapeutic agent(s) act synergistically andare administered in doses lower than the doses commonly employed whensuch agents are used as monotherapy for treating a viral infection.

In one embodiment, the at least one Spirocyclic Heterocycle Compound andthe additional therapeutic agent(s) are present in the same composition.In one embodiment, this composition is suitable for oral administration.In another embodiment, this composition is suitable for intravenousadministration. In another embodiment, this composition is suitable forsubcutaneous administration. In still another embodiment, thiscomposition is suitable for parenteral administration.

Viral infections and virus-related disorders that can be treated orprevented using the combination therapy methods of the present inventioninclude, but are not limited to, those listed above.

In one embodiment, the viral infection is HIV infection.

In another embodiment, the viral infection is AIDS.

The at least one Spirocyclic Heterocycle Compound and the additionaltherapeutic agent(s) can act additively or synergistically. Asynergistic combination may allow the use of lower dosages of one ormore agents and/or less frequent administration of one or more agents ofa combination therapy. A lower dosage or less frequent administration ofone or more agents may lower toxicity of therapy without reducing theefficacy of therapy.

In one embodiment, the administration of at least one SpirocyclicHeterocycle Compound and the additional therapeutic agent(s) may inhibitthe resistance of a viral infection to these agents.

As noted above, the present invention is also directed to use of acompound of Formula I with one or more anti-HIV agents. An “anti-HIVagent” is any agent which is directly or indirectly effective in theinhibition of HIV reverse transcriptase or another enzyme required forHIV replication or infection, the treatment or prophylaxis of HIVinfection, and/or the treatment, prophylaxis or delay in the onset orprogression of AIDS. It is understood that an anti-HIV agent iseffective in treating, preventing, or delaying the onset or progressionof HIV infection or AIDS and/or diseases or conditions arising therefromor associated therewith. For example, the compounds of this inventionmay be effectively administered, whether at periods of pre-exposureand/or post-exposure, in combination with effective amounts of one ormore anti-HIV agents selected from HIV antiviral agents,imunomodulators, antiinfectives, or vaccines useful for treating HIVinfection or AIDS. Suitable HIV antivirals for use in combination withthe compounds of the present invention include, for example, thoselisted in Table A as follows:

TABLE A Name Type abacavir, ABC, Ziagen ® nRTI abacavir + lamivudine,Epzicom ® nRTI abacavir + lamivudine + zidovudine, Trizivir ® nRTIamprenavir, Agenerase ® PI atazanavir, Reyataz ® PI AZT, zidovudine,azidothymidine, Retrovir ® nRTI darunavir, Prezista ® PI ddC,zalcitabine, dideoxycytidine, Hivid ® nRTI ddI, didanosine,dideoxyinosine, Videx ® nRTI ddI (enteric coated), Videx EC ® nRTIdelavirdine, DLV, Rescriptor ® nnRTI Dolutegravir InI efavirenz, EFV,Sustiva ®, Stocrin ® nnRTI efavirenz + emtricitabine + tenofovir DF,Atripla ® nnRTI + nRTI Elvitegravir InI emtricitabine, FTC, Emtriva ®nRTI emtricitabine + tenofovir DF, Truvada ® nRTI emvirine, Coactinon ®nnRTI enfuvirtide, Fuzeon ® FI enteric coated didanosine, Videx EC ®nRTI etravirine, TMC-125 nnRTI fosamprenavir calcium, Lexiva ® PIindinavir, Crixivan ® PI lamivudine, 3TC, Epivir ® nRTI lamivudine +zidovudine, Combivir ® nRTI lopinavir PI lopinavir + ritonavir,Kaletra ® PI maraviroc, Selzentry ® EI nelfmavir, Viracept ® PInevirapine, NVP, Viramune ® nnRTI raltegravir, MK-0518, Isentress ® InIrilpivirine, TMC-278 nnRTI ritonavir, Norvir ® PI saquinavir,Invirase ®, Fortovase ® PI stavudine, d4T, didehydrodeoxythymidine,Zerit ® nRTI tenofovir DF (DF = disoproxil fumarate), TDF, nRTI Viread ®tipranavir, Aptivus ® PI EI = entry inhibitor; FI = fusion inhibitor;InI = integrase inhibitor; PI = protease inhibitor; nRTI = nucleosidereverse transcriptase inhibitor; nnRTI = non-nucleoside reversetranscriptase inhibitor. Some of the drugs listed in the table are usedin a salt form; e.g., abacavir sulfate, indinavir sulfate, atazanavirsulfate, nelfmavir mesylate.

In one embodiment, the one or more anti-HIV drugs are selected fromraltegravir, lamivudine, abacavir, ritonavir, dolutegravir, darunavir,atazanavir, emtricitabine, tenofovir, elvitegravir, rilpivirine andlopinavir.

In another embodiment, the compound of formula (I) is used incombination with a single anti-HIV drug which is raltegravir.

In another embodiment, the compound of formula (I) is used incombination with a single anti-HIV drug which is lamivudine.

In still another embodiment, the compound of formula (I) is used incombination with a single anti-HIV drug which is atazanavir.

In another embodiment, the compound of formula (I) is used incombination with a single anti-HIV drug which is darunavir.

In another embodiment, the compound of formula (I) is used incombination with a single anti-HIV drug which is rilpivirine.

In yet another embodiment, the compound of formula (I) is used incombination with a single anti-HIV drug which is dolutegravir.

In another embodiment, the compound of formula (I) is used incombination with a single anti-HIV drug which is elvitegravir.

In one embodiment, the compound of formula (I) is used in combinationwith two anti-HIV drugs which are lamivudine and abacavir.

In another embodiment, the compound of formula (I) is used incombination with two anti-HIV drugs which are darunavir and raltegravir.

In another embodiment, the compound of formula (I) is used incombination with two anti-HIV drugs which are emtricitabine andtenofovir.

In still another embodiment, the compound of formula (I) is used incombination with two anti-HIV drugs which are atazanavir andraltegravir.

In another embodiment, the compound of formula (I) is used incombination with two anti-HIV drugs which are ritonavir and lopinavir.

In another embodiment, the compound of formula (I) is used incombination with two anti-HIV drugs which are lamivudine andraltegravir.

In one embodiment, the compound of formula (I) is used in combinationwith three anti-HIV drug which are abacavir, lamivudine and raltegravir.

In another embodiment, the compound of formula (I) is used incombination with three anti-HIV drug which are lopinavir, ritonavir andraltegravir.

In one embodiment, the present invention provides pharmaceuticalcompositions comprising (i) a compound of formula (I) or apharmaceutically acceptable salt thereof; (ii) a pharmaceuticallyacceptable carrier; and (iii) one or more additional anti-HIV agentsselected from lamivudine, abacavir, ritonavir and lopinavir, or apharmaceutically acceptable salt thereof, wherein the amounts present ofcomponents (i) and (iii) are together effective for the treatment orprophylaxis of infection by HIV or for the treatment, prophylaxis, ordelay in the onset or progression of AIDS in the subject in needthereof.

In another embodiment, the present invention provides a method for thetreatment or prophylaxis of infection by HIV or for the treatment,prophylaxis, or delay in the onset or progression of AIDS in a subjectin need thereof, which comprises administering to the subject (i) acompound of formula (I) or a pharmaceutically acceptable salt thereofand (ii) one or more additional anti-HIV agents selected fromlamivudine, abacavir, ritonavir and lopinavir, or a pharmaceuticallyacceptable salt thereof, wherein the amounts administered of components(i) and (ii) are together effective for the treatment or prophylaxis ofinfection by HIV or for the treatment, prophylaxis, or delay in theonset or progression of AIDS in the subject in need thereof.

It is understood that the scope of combinations of the compounds of thisinvention with anti-HIV agents is not limited to the HIV antiviralslisted in Table A, but includes in principle any combination with anypharmaceutical composition useful for the treatment or prophylaxis ofAIDS. The HIV antiviral agents and other agents will typically beemployed in these combinations in their conventional dosage ranges andregimens as reported in the art, including, for example, the dosagesdescribed in the Physicians' Desk Reference, Thomson PDR, Thomson PDR,57^(th) edition (2003), the 58^(th) edition (2004), the 59^(th) edition(2005), and the like. The dosage ranges for a compound of the inventionin these combinations are the same as those set forth above.

The doses and dosage regimen of the other agents used in the combinationtherapies of the present invention for the treatment or prevention ofHIV infection can be determined by the attending clinician, taking intoconsideration the approved doses and dosage regimen in the packageinsert; the age, sex and general health of the subject; and the type andseverity of the viral infection or related disease or disorder. Whenadministered in combination, the Spirocyclic Heterocycle Compound(s) andthe other agent(s) can be administered simultaneously (i.e., in the samecomposition or in separate compositions one right after the other) orsequentially. This particularly useful when the components of thecombination are given on different dosing schedules, e.g., one componentis administered once daily and another component is administered everysix hours, or when the preferred pharmaceutical compositions aredifferent, e.g., one is a tablet and one is a capsule. A kit comprisingthe separate dosage forms is therefore advantageous.

Compositions and Administration

When administered to a subject, the Spirocyclic Heterocycle Compoundscan be administered as a component of a composition that comprises apharmaceutically acceptable carrier or vehicle. The present inventionprovides pharmaceutical compositions comprising an effective amount ofat least one Spirocyclic Heterocycle Compound and a pharmaceuticallyacceptable carrier. In the pharmaceutical compositions and methods ofthe present invention, the active ingredients will typically beadministered in admixture with suitable carrier materials suitablyselected with respect to the intended form of administration, L e., oraltablets, capsules (either solid-filled, semi-solid filled or liquidfilled), powders for constitution, oral gels, elixirs, dispersiblegranules, syrups, suspensions, and the like, and consistent withconventional pharmaceutical practices. For example, for oraladministration in the form of tablets or capsules, the active drugcomponent may be combined with any oral non-toxic pharmaceuticallyacceptable inert carrier, such as lactose, starchours, sucrose,cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate,talc, mannitol, ethyl alcohol (liquid forms) and the like. Solid formpreparations include powders, tablets, dispersible granules, capsules,cachets and suppositories. Powders and tablets may be comprised of fromabout 0.5 to about 95 percent inventive composition. Tablets, powders,cachets and capsules can be used as solid dosage forms suitable for oraladministration.

Moreover, when desired or needed, suitable binders, lubricants,disintegrating agents and coloring agents may also be incorporated inthe mixture. Suitable binders include starchours, gelatin, naturalsugars, corn sweeteners, natural and synthetic gums such as acacia,sodium alginate, carboxymethylcellulose, polyethylene glycol and waxes.Among the lubricants there may be mentioned for use in these dosageforms, boric acid, sodium benzoate, sodium acetate, sodium chloride, andthe like. Disintegrants include starchours, methylcellulose, guar gum,and the like. Sweetening and flavoring agents and preservatives may alsobe included where appropriate.

Liquid form preparations include solutions, suspensions and emulsionsand may include water or water-propylene glycol solutions for parenteralinjection.

Liquid form preparations may also include solutions for intranasaladministration.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for eitheroral or parenteral administration. Such liquid forms include solutions,suspensions and emulsions.

For preparing suppositories, a low melting wax such as a mixture offatty acid glycerides or cocoa butter is first melted, and the activeingredient is dispersed homogeneously therein as by stirring. The moltenhomogeneous mixture is then poured into convenient sized molds, allowedto cool and thereby solidify.

Additionally, the compositions of the present invention may beformulated in sustained release form to provide the rate controlledrelease of any one or more of the components or active ingredients tooptimize therapeutic effects, i.e., antiviral activity and the like.Suitable dosage forms for sustained release include layered tabletscontaining layers of varying disintegration rates or controlled releasepolymeric matrices impregnated with the active components and shaped intablet form or capsules containing such impregnated or encapsulatedporous polymeric matrices.

In one embodiment, the one or more Spirocyclic Heterocycle Compounds areadministered orally.

In another embodiment, the one or more Spirocyclic Heterocycle Compoundsare administered intravenously.

In one embodiment, a pharmaceutical preparation comprising at least oneSpirocyclic Heterocycle Compound is in unit dosage form. In such form,the preparation is subdivided into unit doses containing effectiveamounts of the active components.

Compositions can be prepared according to conventional mixing,granulating or coating methods, respectively, and the presentcompositions can contain, in one embodiment, from about 0.1% to about99% of the Spirocyclic Heterocycle Compound(s) by weight or volume. Invarious embodiments, the present compositions can contain, in oneembodiment, from about 1% to about 70% or from about 5% to about 60% ofthe Spirocyclic Heterocycle Compound(s) by weight or volume.

The compounds of Formula I can be administered orally in a dosage rangeof 0.001 to 1000 mg/kg of mammal (e.g., human) body weight per day in asingle dose or in divided doses. One preferred dosage range is 0.01 to500 mg/kg body weight per day orally in a single dose or in divideddoses. Another preferred dosage range is 0.1 to 100 mg/kg body weightper day orally in single or divided doses. For oral administration, thecompositions can be provided in the form of tablets or capsulescontaining 1.0 to 500 milligrams of the active ingredient, particularly1, 5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, and 500milligrams of the active ingredient for the symptomatic adjustment ofthe dosage to the subject to be treated. The specific dose level andfrequency of dosage for any particular subject may be varied and willdepend upon a variety of factors including the activity of the specificcompound employed, the metabolic stability and length of action of thatcompound, the age, body weight, general healthours, sex, diet, mode andtime of administration, rate of excretion, drug combination, theseverity of the particular condition, and the host undergoing therapy.

For convenience, the total daily dosage may be divided and administeredin portions during the day if desired. In one embodiment, the dailydosage is administered in one portion. In another embodiment, the totaldaily dosage is administered in two divided doses over a 24 hour period.In another embodiment, the total daily dosage is administered in threedivided doses over a 24 hour period. In still another embodiment, thetotal daily dosage is administered in four divided doses over a 24 hourperiod.

The amount and frequency of administration of the SpirocyclicHeterocycle Compounds will be regulated according to the judgment of theattending clinician considering such factors as age, condition and sizeof the subject as well as severity of the symptoms being treated. Thecompositions of the invention can further comprise one or moreadditional therapeutic agents, selected from those listed above herein.

Kits

In one aspect, the present invention provides a kit comprising atherapeutically effective amount of at least one Spirocyclic HeterocycleCompound, or a pharmaceutically acceptable salt or prodrug of saidcompound and a pharmaceutically acceptable carrier, vehicle or diluent.

In another aspect the present invention provides a kit comprising anamount of at least one Spirocyclic Heterocycle Compound, or apharmaceutically acceptable salt or prodrug of said compound and anamount of at least one additional therapeutic agent listed above,wherein the amounts of the two or more active ingredients result in adesired therapeutic effect. In one embodiment, the one or moreSpirocyclic Heterocycle Compounds and the one or more additionaltherapeutic agents are provided in the same container. In oneembodiment, the one or more Spirocyclic Heterocycle Compounds and theone or more additional therapeutic agents are provided in separatecontainers.

Methods for Making the Compounds of Formula (I)

The Compounds of Formula (I) may be prepared from known or readilyprepared starting materials, following methods known to one skilled inthe art of organic synthesis. Methods useful for making the Compounds ofFormula (I) are set forth in the Examples below and generalized inScheme 1 below. Alternative synthetic pathways and analogous structureswill be apparent to those skilled in the art of organic synthesis.

Scheme 1 describes methods useful for making the Compounds of Formula(I).

Compounds of Formula (I) can be prepared as shown in Scheme 1 from a3-hydroxy-4-oxo-4H-pyran-2-carboxylic acid that is mono-protected as the3-methoxy- or 3-benzyloxy ether (R¹=Me or Bn) and a suitablyfuntionalized 1,2-vicinal diamine which are converted to compound A bystandard coupling techniques. Compound A is then deprotected andsubjected to cyclization conditions to provide a mixture of structuralisomers B-1 and B-2 that are separated by standard chromatographytechniques. Halogen transfer to compound B-1 affords compound C (X=I orBr or Cl). Compound C is then alkylated to provide compound D which isthen carbonylated with a transition metal catalyst system in thepresence of a suitably functionalized amine and carbon monoxide toprovide Compound E. Deprotection of Compound E affords final compound F.

An additional variation involves amino transfer to compound C whichaffords compound G. Alkylation of compound G affords compound H which issubjected to carbonylated with a transition metal catalyst system in thepresence of a suitably functionalized amine and carbon monoxide toprovide Compound I. Deprotection of Compound I affords final compound J.

Compounds of Formula (I) can also be prepared as shown in Scheme 2 froma 3-hydroxy-4-oxo-4H-pyran-2-carboxylic acid that is mono-protected asthe 3-methoxy- or 3-benzyloxy ether (R¹=Me or Bn) and a suitablyfuntionalized 1,2-vicinal amino alcohol which are cyclized to providecompound A. Amidation of compound A affords compound B which is oxidizedto provide compound C. Compound C can be halogenated (X=I or Br or Cl)to provide compound D which is then alkylated to provide compound E.Carbonylated of compound E with a transition metal catalyst system inthe presence of a suitably functionalized amine and carbon monoxideaffords Compound F which is deprotected to provide final compound G.

Compounds of Formula (I) can also be prepared as shown in Scheme 3 froma suitably functionalized compound A (X=I or Br or Cl). Alkylation ofcompound A affords compound B which is then carbonylated with a suitablyfunctionalized alcohol and carbon monoxide in the presence of atransition metal catalyst system to provide compound C. Hydrolysis ofcompound C affords compound D which is coupled to a suitablyfunctionalized acyl hydrazide under standard amide-formation conditionsto provide compound E. A sulfur transfer reagent (e.g., Lawesson'sreagent) effects the cyclization of compound E to provide compound Fwhich is deprotected to provide compound G.

EXAMPLES

General Methods

The compounds described herein can be prepared according to theprocedures of the following schemes and examples, using appropriatematerials and are further exemplified by the following specificexamples. The compounds illustrated in the examples are not, however, tobe construed as forming the only genus that is considered as theinvention. The examples further illustrate details for the preparationof the compounds of the present invention. Those skilled in the art willreadily understand that known variations of the conditions and processesof the following preparative procedures can be used to prepare thesecompounds. Concentration refers to the removal of the volatilecomponents at reduced pressure (e.g. rotary evaporation) unlessotherwise noted. All temperatures are degrees Celsius unless otherwisenoted. Mass spectra (MS) were measured by electrospray ion-massspectroscopy (ESI) in positive ion detection mode and m/z refers to the[M+H]⁺ ion unless otherwise noted. ¹H NMR spectra were recorded at400-500 MHz at ambient temperature unless otherwise noted. RP-HPLCrefers to reverse phase HPLC on C18-functionalized preparative orsemi-preparative columns with gradient elution using acetonitrile andwater modified with trifluoroacetic acid as eluents and fractions werelyophylized or concentrated by rotary evaporation unless otherwisenoted. Compounds described herein were synthesized as the racematesunless otherwise noted in the experimental procedures and compoundtables. For stereoisomers, enantiomer A refers to the earlier elutingenantiomer and enantiomer B refers to the later eluting enantiomer atthe point of chiral resolution and this nomenclature is maintainedthrough the remainder of a synthetic sequence for a given enantiomericseries despite the possibility that subsequent intermediates and finalcompounds may have the same or opposite orders of elution.

Example 1 Preparation of Compound 1

Step A—Synthesis of Intermediate Compound Int-1a

A solution of 3-(aminomethyl)-N,N-dibenzyloxetan-3-amine (5.00 g, 17.7mmol) in THF (50 mL) was treated with aqueous solution of Na₂CO₃ (5.63g, 53.1 mmol) in water (25 mL) and a solution of di-tert-butyldicarbonate (4.64 g, 21.5 mmol) in THF (10 mL). The mixture was allowedto stir at 20° C. for 5 hours, diluted with water (100 mL) and extractedwith dichloromethane (50 mL×3). The organic layer was dried overanhydrous sodium sulfate and filtered. The filtrate was concentrated invacuo to provide Int-la that was used without further purification. ¹HNMR (400 MHz, CDCl₃) δ 7.21-7.32 (m, 10H), 4.47 (d, J=6.0 Hz, 2H), 4.01(d, J=6.4 Hz, 2H), 3.76 (d, J=6.0 Hz, 2H), 3.65 (s, 4H), 1.51 (s, 9H).

Step B—Synthesis of Intermediate Compound Int-1b

A solution of Int-1a (5200 mg, 13.59 mmol) in methanol (50 mL) wastreated with 20% Pd(OH)₂/C (2000 mg, 2.85 mmol) and 0.5 mLtrifluoroacetic acid. The mixture was stirred under H₂ (1 atm) at 15° C.for 16 hours and then filtered. The filtrate was concentrated in vacuoto provide crude Int-1b, which was used in the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 5.17 (s, 1H), 4.46 (d, J=6.0 Hz,2H), 4.38 (d, J=6.8 Hz, 2H), 3.40-3.45 (m, 2H), 2.28 (s, 2H), 1.41 (s,9H).

C—Synthesis of Intermediate Compound Int-1c

A solution of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (2400 mg,9.75 mmol) in N,N-dimethylformamide (30 mL) was treate with PyClu (4570mg, 12.57 mmol), diisopropylamine (3.4 mL, 19.5 mmol) and Int-1b (2400mg, 9.75 mmol). The mixture was allowed to stir at 15° C. for 16 hours,diluted with water (50 mL) and extracted with ethyl acetate (30 mL×3).The organic layers were washed with brine (100 mL), dried over anhydroussodium sulfate, and then filtered. The filtrate was concentrated invacuo and the resulting residue was purified using column chromatography(petroleum ether: ethyl acetate=1:1) to provide Int-1c. ¹H NMR (400 MHz,CDCl₃) δ 8.11 (s, 1H), 7.81 (d, J=6.0 Hz, 1H), 7.41 (m, 5H), 6.49 (d,J=5.6 Hz, 1H), 5.47 (s, 2H), 4.85 (s, 1H), 4.42 (d, J=6.4 Hz, 2H), 4.25(d, J=6.4 Hz, 2H), 3.64 (d, J=6.0 Hz, 2H), 1.41 (s, 9H). MS (+ESI) m/z:431.1.

Step D—Synthesis of Intermediate Compound Int-1d

A solution of Int-1c (2400 mg, 5.58 mmol) indichloromethane:trifluoroacetic acid=4:1(30 mL) was allowed to stir at20° C. for 2 hours and then concentrated in vacuo. The crude residue wasresolved in ethanol (60 mL), sealed in a microwave tube and irradiated(microwave) with stirring at 90° C. for 2 hours. The mixture wasconcentrated in vacuo and the resulting residue was purified usingpreparative TLC on silica gel (dichloromethane:methanol=10:1) to provideInt-1d. ¹H NMR (400 MHz, CDCl₃) δ 7.56 (s, 1H), 7.43 (d, J=6.4 Hz, 2H),7.21-7.30 (m, 3H), 6.46 (d, J=7.6 Hz, 1H), 5.28 (s, 2H), 4.59 (d, J=7.2Hz, 2H), 4.36 (d, J=7.2 Hz, 2H), 4.22 (s, 2H). MS (+ESI) m/z: 313.2.

Step E—Synthesis of Intermediate Compound Int-1e

A solution of Int-1d (312 mg, 0.224 mmol) in dichloromethane (3 mL) wastreated with N-bromosuccinimide (80 mg, 0.448 mmol) at 0° C. The mixturewas allowed to stir at 20° C. for 1 hour and then purified usingpreparative TLC on silica gel (dichloromethane:methanol=10: 1) toprovide Int-1e. ¹H NMR (400 MHz, methanol-d4) δ 8.73 (s, 1H), 7.49 (d,J=6.4 Hz, 2H), 7.30 (d, J=7.6 Hz, 3H), 5.17 (s, 2H), 5.05 (d, J=8.0 Hz,2H), 4.63 (d, J=8.4 Hz, 2H), 3.81 (s, 2H). MS (+ESI) m/z: 391.9, 392.9

Step F—Synthesis of Intermediate Compound Int-1f

A solution of Int-1e (105 mg, 0.268 mmol) in N,N-dimethylformamide (2mL) was treated with cesium carbonate (525 mg, 1.610 mmol), stirred at20° C. for 30 minutes and then treated withO-(2,4-dinitrophenyl)hydroxylamine (214 mg, 1.074 mmol). The mixture wasallowed to stir at 20° C. for 16 hours and quenched with water (30 mL).The volatile components were removed by lyophilization resulting in ayellow solid that was slurried in dichloromethane (150 mL) and filtered.The filtrate was concentrated in vacuo and the resulting residue waspurified using preparative TLC on silica gel (dichloromethane:methanol=10:1) to provide Int-1f. ¹H NMR (400 MHz, methanol-d4) δ 8.70(s, 1H), 7.52 (m, 2H), 7.32 (m, 3H), 5.17 (s, 2H), 5.05 (d, J=7.6 Hz,2H), 4.66 (d, J=8.0 Hz, 2H), 4.13 (s, 2H).

Step G—Synthesis of Intermediate Compound Int-1g

A solution of Int-1f (150 mg, 0.334 mmol) in N,N-dimethylformamide (2mL) was treated with K₂CO₃ (87 mg, 0.633 mmol) and iodomethane (0.16 mL,2.53 mmol), stirred at 15° C. for 16 hours, diluted with water (10 mL)and extracted with ethyl acetate (15 mL×3). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated invacuo. The resulting residue was purified using preparative TLC onsilica gel (dichloromethane: methanol=15:1) to provide Int-1g. ¹H NMR(400 MHz, methanol-d4) δ 8.72 (s, 1H), 7.53 (d, J=6.4 Hz, 2H), 7.27-7.36(m, 3H), 5.18 (s, 2H), 5.04 (d, J=8.4 Hz, 2H), 4.68 (d, J=8.0 Hz, 2H),4.10 (s, 2H), 2.73 (s, 6H). MS (+ESI) m/z: 434.0, 436.0.

Step H—Synthesis of Intermediate Compound Int-1h

A solution of Int-1g (12 mg, 0.028 mmol) in dimethylsulfoxide (0.5 mL)and methanol (2.0 mL) were treated with (2,4-difluorophenyl)methanamine(19.78 mg, 0.14 mmol), N,N-diisopropylethylamine (9 μL, 0.06 mmol) andPd(Ph₃P)₄ (6.4 mg, 5.5 μmol). The mixture was allowed to stir at 80° C.for 2 hours, cooled to room temperature, diluted with water (10 mL) andextracted with ethyl acetate (15 mL×3). The combined organic layers werewashed with 1M HCl (50 mL), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The resulting residue was purifiedusing preparative TLC on silica gel (ethyl acetate) to provide Int-1h ¹HNMR (400 MHz, CDCl₃) δ 8.87 (s, 1H), 7.52 (d, J=7.2 Hz, 2H), 7.23-7.36(m, 5H), 6.69-6.83 (m, 2H), 5.23 (s, 2H), 4.99 (d, J=8.0 Hz, 2H),4.50-4.61 (m, 4H), 3.93 (s, 2H), 2.78 (s, 6H).

Step I—Synthesis of Compound 1

A solution of Int-1h (8 mg, 18 μmol) in N,N-dimethylformamide (1 mL) wastreated with LiCl (2.4 mg, 0.06 mmol). The mixture was allowed to stirat 100° C. for 2 hours, cooled to room temperature, filtered and thefiltrate was directly purified using RP-HPLC to provide Compound 1. ¹HNMR (400 MHz, DMSO-d₆) δ 12.66 (s, 1H), 10.32 (s., 1H), 8.72 (s., 1H),7.36-7.42 (m, 1H), 7.20-7.26 (m, 1H), 7.06 (d, J=10.0 Hz, 1H), 4.89 (d,J=8.0 Hz, 2H), 4.70 (d, J=8.0 Hz, 2H), 4.50-4.58 (m, 2H), 4.17 (s., 2H),2.67 (s, 6H). MS (+ESI) m/z: 435.1.

The following compound of the present invention was made using themethods described above in Example 1 and substituting the appropriatereactants and reagents:

Com- pound Exact Num- Mass ber Structure [M + H]⁺ 2

Calc'd 463.2, found 463.1

Example 2 Preparation of Compound 3

Step A—Synthesis of Intermediate Compound Int-2a

A solution of Int-1e (69 mg, 0.18 mmol) in N,N-dimethylformamide (2 mL)was added Cs₂CO₃ (172 mg, 0.53 mmol) and 1-bromo-2-methoxyethane (122mg, 0.87 mmol). The mixture was allowed to stir at 15° C. for 6 hours,diluted with water (15 mL) and extracted with ethyl acetate (10 mL×3).The combined organic layers were washed with brine (50 mL), dried overanhydrous sodium sulfate, filtered and concentrated in vacuo. Theresulting residue was purified using preparative TLC on silica gel(dichloromethane:methanol=10:1) to provide Int-2a. ¹H NMR (400 MHz,CDCl₃) δ 8.17 (s, 1H), 8.01 (s, 1H), 7.61 (d, J=7.2 Hz, 2H), 7.29-7.42(m, 3H), 5.12 (s, 2H), 4.69-4.81 (m, 4H), 4.05 (s, 2H), 3.51 (t, J=4.50Hz, 2H), 3.38 (t, J=4.4 Hz, 2H), 3.31 (s, 3H). MS (+ESI) m/z: 449.0.

Step B—Synthesis of Intermediate Compound Int-2b

A solution of Int-2a (46 mg, 0.099 mmol) in dimethylsulfoxide (0.5 mL)and methanol (2.0 mL) was treated with (2,4-difluorophenyl)methanamine(112 mg, 0.50 mmol), N,N-diisopropylethylamine (0.05 mL, 0.30 mmol) andPd(Ph₃P)₄ (24 mg, 0.020 mmol). The mixture was allowed to stir at 80° C.under carbon monoxide (1 atm) for 6 hours, diluted with water (10 mL)and extracted with ethyl acetate (10 mL×3). The combined organic layerswere washed with 1M HCl (30 mL), dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The resulting residue was purifiedusing preparative TLC on silica gel (dichloromethane:methanol=15:1) toprovide Int-2b. ¹H NMR (400 MHz, methanol-d4) δ 8.93 (s, 1H), 7.42-7.55(m, 3H), 7.29 (bs, 3H), 6.87-7.01 (m, 2H), 5.12 (s, 2H), 4.95 (d, J=7.6Hz, 2H), 4.69 (d, J=7.6 Hz, 2H), 4.63 (s, 1H), 4.04 (s, 2H), 3.55-3.70(m, 4H), 3.34 (s, 3H), 3.29 (s, 2H). MS (+ESI) m/z: 540.2.

Step C—Synthesis of Compound 3

A solution of Int-2b (20 mg, 0.037 mmol) in N,N-dimethylformamide (2 mL)was treated with lithium chloride (16 mg, 0.37 mmol) at rt. The mixturewas allowed to stir at 100° C. for 2 hours, cooled to room temperature,filtered and the filtrate was directly purified using RP-HPLC to provideCompound 3. ¹H NMR (400 MHz, CDCl₃) δ 12.59 (s, 1H), 10.38 (s, 1H), 8.89(s, 1H), 7.34-7.43 (m, 1H), 6.77-6.88 (m, 2H), 5.03 (d, J=7.6 Hz, 2H),4.67 (d, J=7.2 Hz, 4H), 4.20 (s, 2H), 3.80 (t, J=4.4 Hz, 2H), 3.64-3.71(m, 2H), 3.39 (s, 3H). MS (+ESI) m/z: 450.1.

The following compounds of the present invention were made using themethods described above in Example 2 and substituting the appropriatereactants and reagents:

Com- pound Exact Num- Mass ber Structure [M + H]⁺ 4

Calc'd 406.1, found 406.3 5

Calc'd 420.1, found 420.1

Example 3 Preparation of Compound 6

Step A—Synthesis of Intermediate Compound Int-3a

A solution of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (1.1 g,4.47 mmol), PyClu (1.783 g, 5.36 mmol),4-(aminomethyl)tetrahydro-2H-pyran-4-amine (0.872 g, 6.70 mmol) andN,N-diisopropylethylamine (1.155 g, 8.94 mmol) in THF (20 mL) wasallowed to stir at 15° C. for 3 hours. The mixture was quenched withwater (30 mL) and extracted with ethyl acetate (50 mL×3). The combinedorganic layers were washed with brine (10 mL), dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The resultingresidue was purified using column chromatography on silica gel(dichloromethane/methanol=10/1) to provide Int-3a: ¹H NMR (400 MHz,CDCl₃) δ 8.15 (br, s, 1H), 7.83-7.84 (d, J=5.2 Hz, 1H), 7.37-7.43 (m,5H), 6.48-6.49 (d, J=5.2 Hz, 1H), 5.45 (s, 2H), 3.61-3.64 (m, 4H),3.22-3.24 (d, J=6 Hz, 2H), 1.63-1.80 (m, 2H), 1.45-1.51 (m, 2H).

Step B—Synthesis of Intermediate Compound Int-3b

A suspension of Int-3a and NaHCO₃ (293 mg, 3.49 mmol) in water (5 mL)was allowed to stir at 100° C. for 3 hours. The reaction mixture wascooled to room temperature and concentrated in vacuo. The resultingresidue was purified using preparative TLC on silica gel(dichloromethane/methanol=10/1) to provide Int-3b. ¹H NMR (400 MHz,methanol-d4) δ 7.68-7.70 (d, J=7.6 Hz, 1H), 7.24-7.34 (m, 5H), 6.51-6.53(d, J=7.6 Hz, 1H), 5.29 (s, 2H), 4.07 (s, 2H), 3.56-3.66 (m, 4H),1.52-1.56 (m, 2H), 1.22-1.26 (m, 2H).

Step C—Synthesis of Intermediate Compound Int-3c

A solution of Int-3b (90 mg, 0.21 mmol) in dichloromethane (5 mL) wastreated with N-bromosuccinimide (52.3 mg, 0.294 mmol), stirred at 20° C.for 3 hours and concentrated at low temperature. The resulting residuewas purified using preparative TLC on silica gel(dichloromethane/methanol=10/1) to provide Int-3c. ¹H NMR (400 MHz,methanol-d4) δ 8.47 (s, 1H), 7.50-7.51 (m, 2H), 7.30-7.32 (m, 3H), 5.19(s, 2H), 3.96-3.98 (m, 2H), 3.65-3.68 (m, 4H), 2.34-2.36 (m, 2H),1.89-1.93 (m, 2H).

Step D—Synthesis of Intermediate Compound Int-3d

A solution of Int-3c (90 mg, 0.20 mmol) in N,N-dimethylformamide (4 mL)was treated with cesium carbonate (62.2 mg, 0.19 mmol) and1-bromo-2-methoxyethane (19.9 mg, 0.14 mmol). The mixture was allowed tostir at 20° C. for 5 hours and concentrated in vacuo. The resultingresidue was purified using preparative TLC on silica gel(dichloromethane/methanol=10/1) to provide Int-3d. ¹H NMR (400 MHz,methanol-d4) δ 8.49 (s, 1H), 7.47-7.49 (m, 2H), 7.31-7.32 (m, 3H), 5.18(s, 2H), 3.94-3.97 (m, 2H), 3.88 (s, 2H), 3.62-3.72 (m, 6H), 3.34 (s,3H), 2.30-2.36 (m, 2H), 1.86-1.89 (m, 2H).

Step E—Synthesis of Intermediate Compound Int-3e

A solution of Int-3d (5 mg, 10 μmol), N,N-diisopropylethylamine (0.018mL, 0.105 mmol), (2,4-difluorophenyl)methanamine (7.5 mg, 0.05 mmol),Pd(Ph₃P)₄ (6.0 mg, 5 μmol) in methanol (0.5 mL) and dimethylsulfoxide(1.5 mL) was allowed to stir at 80° C. under carbon monoxide (1 atm) for16 hours. The mixture was cooled to room temperature, diluted with water(3 mL) and extracted with ethyl acetate (10 mL×3). The combined organiclayers were washed with 1N aq HCl (3 mL), dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The resulting residue waspurified using preparative TLC on silica gel(dichloromethane/methanol=20/1) to provide Int-3e. ¹H NMR (400 MHz,methanol-d4) δ 8.77 (s, 1H), 7.30-7.49 (m, 6H), 6.89-7.00 (m, 2H), 5.17(s, 2H), 4.63-4.65 (d, J=5.2 Hz, 2H), 3.87-3.93 (m, 2H), 3.75 (s, 3H),3.61-3.70 (m, 6H), 3.34 (s, 3H), 2.25-2.32 (m, 2H), 1.91-2.00 (m, 2H).MS (+ESI) m/z: 568.2.

Step F—Synthesis of Compound 6

A solution of Int-3e (15 mg, 0.026 mmol) in N,N-dimethylformamide (3 mL)was treated with lithium chloride (11.2 mg, 0.26 mmol), stirred at 100°C. for 2 hours, filtered and the filtrate was directly purified usingRP-HPLC to provide Compound 6. ¹H NMR (400 MHz, methanol-d4) δ 8.63 (s,1H), 7.33-7.35 (m, 1H), 6.82-6.89 (m, 2H), 4.54 (s, 2H), 3.96 (s, 2H),3.82-3.88 (m, 2H), 3.57-3.72 (m, 6H), 3.25 (s, 3H), 2.16-2.21 (m, 2H),1.87-2.94 (m, 2H). MS (+ESI) m/z: 478.2.

The following compound of the present invention was made using themethods described above in Example 3 and substituting the appropriatereactants and reagents:

Com- pound Exact Num- Mass ber Structure [M + H]⁺ 7

Calc'd 434.2, found 434.0

Example 4 Preparation of Compounds 8 and 9

Step A—Synthesis of Intermediate Compound Int-4a

A mixture of dihydro-2H-pyran-3(4H)-one (256 mg, 3.19 mmol) andphenylmethanamine (302 mg, 2.81 mmol) was allowed to stir at 20° C. for5 minutes, cooled 0° C. and treated dropwise withtrimethylsilanecarbonitrile (305 mg, 3.07 mmol). After addition, themixture was allowed to stir at 20° C. for 15 hours. The reaction mixturewas directly purified using column chromatography on silica gel(petroleum ether:ethyl acetate=5:1) to provide Int-4a ¹H NMR (400 MHz,CDCl₃) δ 7.27-7.43 (m, 5H), 4.03 (dd, J=1.6, 11.2 Hz, 1H), 3.92-4.00 (m,2H), 3.83-3.91 (m, 1H), 3.45 (dt, J=2.2, 11.0 Hz, 1H), 3.36 (d, J=11.3Hz, 1H), 2.21 (d, J=12.1 Hz, 1H), 1.89-2.02 (m, 1H), 1.72-1.83 (m, 2H).

Step B—Synthesis of Intermediate Compound Int-4b

A mixture of Int-4a (500 mg, 2.29 mmol) in THF (10 mL) at 0° C. wastreated with lithium aluminum hydride (130 mg, 3.44 mmol). Afteraddition, the mixture was allowed to stir at 0° C. for 2 hours, quenchedby water (2 mL), filtered and the filtrate was concentrated in vacuo toprovide Int-4b that was used without further purification. ¹H NMR (400MHz, CDCl₃) δ 7.30-7.40 (m, 5H), 3.72-3.84 (m, 2H), 3.64 (d, J=3.7 Hz,2H), 3.46-3.55 (m, 1H), 3.38 (d, J=11.2 Hz, 1H), 2.69-2.77 (m, 1H),2.53-2.64 (m, 1H), 1.78-1.87 (m, 1H), 1.66-1.74 (m, 2H), 1.42-1.51 (m,1H).

Step C—Synthesis of Intermediate Compound Int-4c

A mixture of Int-4b (434 mg, 1.97 mmol), trifluoroacetic acid (0.15 mL,1.97 mmol) and Pd(OH)₂ (138 mg, 0.197 mmol) in methanol (8 mL) wasallowed to stir at 50° C. under H₂ (15 psi) for 36 hours and thenfiltered and the filtrate was concentrated in vacuo to provide Int-4cthat was used without further purification. ¹H NMR (400 MHz, CDCl₃) δ3.63-3.89 (m, 2H), 3.55 (d, J=7.6 Hz, 1H), 3.31-3.46 (m, 2H), 2.75-2.92(m, 1H), 1.49-1.80 (m, 4H).

Step D—Synthesis of Intermediate Compound Int-4d

A solution of Int-4c (248 mg, 1.91 mmol), N,N-diisopropylethylamine(0.50 ml, 2.87 mmol) and 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid(235 mg, 0.954 mmol) in N,N-dimethylformamide (10 mL) was treated with((6-chloro-1H-benzo[d][1,2,3]triazol-1-yl)oxy)tri(pyrrolidin-1-yl)phosphoniumhexafluoro-phosphate(V) (635 mg, 1.15 mmol) at 20° C., stirred at 20° C. for 4 hours andconcentrated in vacuo. The resulting residue was purified using columnchromatography on silica gel (dichloromethane:ethyl acetate=1:2 thendichloromethane:methanol:Et₃N=20:1:0.4) to provide a crude Int-4d. ¹HNMR (400 MHz, CDCl₃) δ 7.76-7.86 (m, 1H), 7.50 (d, J=7.2 Hz, 1H),7.29-7.42 (m, 5H), 6.49 (d, J=7.6 Hz, 1H), 5.34-5.51 (m, 2H), 4.88-4.99(m, 1H), 4.57-4.65 (m, 1H), 4.29-4.37 (m, 1H), 3.74 (d, J=12.0 Hz, 1H),3.49 (d, J=6.4 Hz, 2H), 2.01-2.07 (m, 2H), 1.84-1.92 (m, 2H). MS (ESI)m/z: 359.2.

Step E—Synthesis of Intermediate Compound Int-4e

A mixture of Int-4d (235 mg, 0.656 mmol) and NaHCO₃ (55 mg, 0.656 mmol)in water (10 mL) was allowed to stir at 100° C. for 1 hour and thenconcentrated in vacuo. The resulting residue was purified using columnchromatography on alumina (dichloromethane: methanol =50: 1) to providecrude Int-4e. ¹H NMR (400 MHz, CDCl₃) δ 8.58 (s, 1H), 7.61 (d, J=7.2 Hz,2H), 7.29-7.36 (m, 3H), 6.68 (br s, 1H), 5.39 (d, J=10.0 Hz, 1H), 5.21(d, J=10.0 Hz, 1H), 3.95-4.05 (m, 2H), 3.71 (d, J=12.8 Hz, 1H),3.43-3.51 (m, 2H), 3.15 (dd, J=5.6, 13.2 Hz, 1H), 2.30 (d, J=13.2 Hz,1H), 1.79-1.83 (m, 3H). MS (ESI) m/z: 341.1.

Step F—Synthesis of Intermediate Compound Int-4f

A mixture of Int-4e (94 mg, 0.275 mmol) and N-bromosuccinimide (147 mg,0.826 mmol) in dichloromethane (4 mL) was allowed to stir at 25° C. for3 hours and then concentrated in vacuo. The resulting residue waspurified using RP-HPLC to provide Int-4f. ¹H NMR (400 MHz, CDCl₃) δ 8.56(s, 1H), 7.61 (d, J=7.0 Hz, 2H), 7.28-7.38 (m, 3H), 6.46 (br s, 1H),5.40 (d, J=9.9 Hz, 1H), 5.21 (d, J=9.9 Hz, 1H), 4.01 (d, J=12.3 Hz, 2H),3.62-3.73 (m, 2H), 3.50 (d, J=13.5 Hz, 1H), 3.07-3.15 (m, 1H), 2.31 (d,J=12.3 Hz, 1H), 1.75-1.86 (m, 3H). MS (ESI) m/z: 419.1, 421.1.

Step G—Synthesis of Intermediate Compound Int-4g

A mixture of Int-4f (50 mg, 0.120 mmol), 1-bromo-2-methoxyethane (84 mg,0.596 mmol) and cesium carbonate (165 mg, 0.358 mmol) inN,N-dimethylformamide (3 mL) was allowed to stir at 25° C. for 16 hours,filtered and the filtrate was concentrated to provide Int-4g. ¹H NMR(400 MHz, CDCl₃) δ 8.58 (s, 1H), 7.66 (d, J=7.0 Hz, 2H), 7.28-7.37 (m,3H), 5.41 (d, J=9.8 Hz, 1H), 5.18 (d, J=9.8 Hz, 1H), 4.02 (d, J=13.8 Hz,2H), 3.54-3.76 (m, 7H), 3.34 (s, 4H), 2.25 (d, J=13.8 Hz, 1H), 1.84-1.91(m, 1H), 1.72-1.79 (m, 2H). MS (ESI) m/z: 477.0, 479.0.

Step H—Synthesis of Intermediate Compound Int-4h-1 and Int-4h-2

A solution of Int-4g (50 mg, 0.105 mmol) in dimethylsulfoxide (5 mL) wastreated with (2,4-difluorophenyl)methanamine (30.0 mg, 0.21 mmol),N,N-diisopropylethylamine (40.6 mg, 0.31 mmol) and Pd(Ph₃P)₄ (60.5 mg,0.05 mmol). The reaction was stirred under carbon monoxide (1 atm) at96° C. for 4 hours, cooled to room temperature, filtered and thefiltrate was concentrated, The resulting residue was purified usingRP-HPLC to provide the intended product as the racemate. ¹H NMR (400MHz, CDCl₃) δ 10.68 (t, J=5.2 Hz, 1H), 9.09 (s, 1H), 7.57 (d, J=7.0 Hz,2H), 7.28-7.42 (m, 4H), 6.82 (d, J=8.8 Hz, 2H), 5.20-5.33 (m, 2H), 4.65(d, J=5.8 Hz, 2H), 3.90-3.95 (m, 1H), 3.85 (br s, 1H), 3.79 (d, J=12.3Hz, 2H), 3.74 (d, J=6.4 Hz, 1H), 3.63-3.71 (m, 3H), 3.55-3.60 (m, 1H),3.49 (d, J=13.8 Hz, 1H), 3.35 (s, 3H), 2.28-2.36 (m, 1H), 1.88-1.98 (m,1H), 1.79 (br s, 2H). MS (ESI) m/z: 568.1. Separation by chiral SFC(Chiralcel OJ-H 250×4.6 mm I.D., Sum; gradient elution with 5% to 40%methanol (0.05% diethylamine) in SC—CO₂; 2.35 mL/min; 220 nm) providedthe earlier eluting Int-4h-1 and the later eluting Int-4h-2.

Step I—Synthesis of Compound 8 and Compound 9

A mixture of Int-4h-1 (15 mg, 0.035 mmol) and lithium chloride (29.9 mg,0.705 mmol) in N,N-dimethylformamide (1 mL) was allowed to stir at 80°C. for 3 hours, cooled to room temperature and directly purified usingRP-HPLC to provide Compound 8. ¹H NMR (400 MHz, CDCl₃) δ 10.52 (br s,1H), 8.92 (s, 1H), 7.31-7.42 (m, 1H), 6.74-6.88 (m, 2H), 4.65 (br s,2H), 3.79-3.95 (m, 5H), 3.58-3.79 (m, 5H), 3.36 (s, 3H), 2.35 (ddd,J=4.6, 8.2, 13.0 Hz, 2H), 1.98 (dd, J=6.6, 12.7 Hz, 2H). MS (ESI) m/z:478.1.

A similar procedure was used to convert Int-4h-2 to Compound 9. ¹H NMR(400 MHz, CDCl₃) δ 10.48 (br s, 1H), 8.90 (s, 1H), 7.32-7.43 (m, 1H),6.72-6.88 (m, 2H), 4.64 (br s, 2H), 3.79-3.94 (m, 5H), 3.60-3.77 (m,5H), 3.36 (s, 3H), 2.34 (ddd, J=4.6, 8.2, 13.2 Hz, 2H), 1.98 (dd, J=6.4Hz, 2H). MS (ESI) m/z: 478.1.

The following compounds of the present invention were made using themethods described above in Example 4 and substituting the appropriatereactants and reagents:

Chiral resolution was accomplished after Step H in Example 4 with SFC(ChiralPak OJ, 5 μm, 250×30 mm I.D. 80:20 SC—CO₂/ethanol(with 0.1%NH₃H₂O), 60 mL/min, 220 nm). Enantiomer A refers to the earlier elutingenantiomer and enantiomer B refers to the later eluting enantiomer.

Com- pound Exact Num- Mass ber Structure [M + H]⁺ 10

Calc'd 434.2, found 434.2 11

Calc'd 434.2, found 434.2

Example 5 Preparation of Compounds 12 and 13

Step A—Synthesis of Intermediate Compound Int-5a

A solution of 3-(aminomethyl)tetrahydrofuran-3-amine (587.5 mg, 5.1mmol) in methanol (10 mL) at 0° C. was treated with triethylamine (2.12mL, 15.2 mmol) Boc₂O (1.41 mL, 6.07 mmol). The mixture was allowed tostir at 15° C. for 5 hours, treated with water (5 mL) and extracted withdichloromethane (10 mL×3). The combined organic layers were washed withbrine (5 mL), dried over anhydrous sodium sulfate and concentrated invacuo to provide Int-5a, which was used without further purification. ¹HNMR (400 MHz, CDCl₃) δ 3.99-4.03 (m, 1H), 3.90-3.92 (m, 1H), 3.48-3.63(m, 2H), 3.22-3.26 (m, 2H), 1.95-1.98 (m, 1H), 1.70-1.75 (m, 1H), 1.39(s, 9H).

Step B—Synthesis of Intermediate Compound Int-5b

A solution of Int-5a (722 mg, 3.34 mmol) in N,N-dimethylformamide (10mL) was treated with N,N-diisopropylethylamine (1.29 g, 10.0 mmol) andHATU (1.904 g, 5.01 mmol), stirred for several minutes and then treatedwith 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (657.55 mg, 2.67mmol). The mixture was allowed to stir at 15° C. for 3 hours, dilutedwith water (5 mL), extracted with ethyl acetate (12 mL×5). The combinedorganic layers were washed with brine (8 mL), dried over anhydroussodium sulfate, filtered, concentrated in vacuo and purified usingchromatography on silica gel (petroleum ether:ethyl acetate=5:1 to 1:1)to provide Int-5b. ¹H NMR (400 MHz, CDCl₃) δ 8.00 (s, 1H), 7.81 (d,J=5.6 Hz, 1H), 7.41 (d, J=10.0 Hz, 5H), 6.48 (d, J=5.2 Hz, 1H),5.41-5.50 (m, 2H), 3.69-3.81 (m, 3H), 3.55-3.58 (m, 1H), 3.50 (d, J=4.2Hz, 2H), 1.91 (s, 1H), 1.66 (s, 1H), 1.42 (s, 9H). MS (+ESI) m/z: 445.0[M+H]⁺, 389.0 [M-tBu]⁺

Step C—Synthesis of Intermediate Compound Int-5c

A solution of Int-5b (1.19 g, 2.67 mmol) in dichloromethane (20 mL) at0° C. was treated with trifluoroacetic acid (4 mL). The mixture wasallowed to stir at 15° C. for 2 hours and then concentrated in vacuo toprovide Int-5c that was used in the next step without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 8.51 (s, 1H), 7.96 (d, J=5.6 Hz,1H), 7.71 (s, 2H), 7.44 (s, 5H), 6.81 (d, J=5.6 Hz, 1H), 5.44-5.55 (m,2H), 3.88-3.93 (m, 1H), 3.70-3.79 (m, 3H), 3.34 (s, 2H), 1.98-2.05 (m,1H), 1.64-1.70 (m, 1H).

Step D—Synthesis of Intermediate Compound Int-5d-1 and IntermediateCompound Int-5d-2

A solution of Int-5c (637.7 mg, 1.848 mmol) in ethanol (15 mL) washeated to reflux for 48 hours, cooled to room temperature andconcentrated in vacuo. The resulting residue was purified usingpreparative TLC on silica gel (dichloromethane:methanol=10:1) to provideInt-5d-1 ¹H NMR (400 MHz, CDCl₃) δ 7.53-7.60 (m, 2H), 7.34 (s, 1H),7.25-7.31 (m, 3H), 6.52 (d, J=7.2 Hz, 1H), 5.35-5.41 (m, 2H), 4.11-4.18(m, 2H), 3.95-3.97 (m, 1H), 3.62-3.64 (m, 1H), 3.48-3.51 (m, 1H),3.22-3.26 (m, 1H), 2.27 (t, J=7.2 Hz, 2H) and Int-5d-2 ¹H NMR (400 MHz,CDCl₃) δ 7.49-7.53 (m, 2H), 7.27-7.29 (m, 3H), 7.19 (d, J=7.2 Hz, 1H),6.50 (d, J=7.2 Hz, 1H), 5.33-5.43 (m, 2H), 3.93 (s, 4H), 3.43-3.61 (m,2H), 1.94 (t, J=8.0 Hz, 2H).

Step E—Synthesis of Intermediate Compound (±)-Int-5e

A solution of Int-5d-1 (88.65 mg, 0.271 mmol) in dichloromethane (6 mL)at 0° C. was treated with N-bromosuccinimide (120.8 mg, 0.678 mmol). Themixture was allowed to stir at 18° C. for 10 hours, quenched withaqueous sodium sulfite (3 mL), diluted with water (3 mL) and extractedwith dichloromethane (5 mL×4). The combined organic layers were washedwith brine (5 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The crude residue was purified using flashchromatography on silica gel (dichloromethane: methanol=15:1 to 10:1) toprovide (±)-Int-5e. ¹H NMR (400 MHz, methanol-d4) δ 8.24 (s, 1H), 7.52(d, J=6.0 Hz, 2H), 7.31 (d, J=7.6 Hz, 3H), 5.14-5.25 (m, 2H), 4.32 (d,J=10.8 Hz, 1H), 4.16-4.19 (m, 1H), 3.99-4.01 (m, 1H), 3.78 (d, J=11.2Hz, 1H), 3.60 (d, J=13.6 Hz, 1H), 3.47 (d, J=14.4 Hz, 1H), 2.38-2.64 (m,2H). Chiral resolution to provide the separated enantiomers wasaccomplished with SFC (Chiralpak AD, 50% methanol in SC—CO₂; 220 nm) toprovide the separated enantiomers Int-5e-1 (enantiomer A) and Int-5e-2(enantiomer B).

Step F—Synthesis of Intermediate Compound Int-5f

A solution of (±)-Int-5e (62.9 mg, 0.155 mmol) in N,N-dimethylformamide(6 mL) was treated with cesium carbonate (151.9 mg, 0.466 mmol) and1-bromo-3-methoxypropane (47.54 mg, 0.311 mmol). The mixture was allowedto stir at 50° C. for 4 hours, quenched with water (3 mL) and extractedwith ethyl acetate (10 mL×3). The combined organic layers were washedwith brine (10 mL×2), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The resulting residue was purified usingpreparative TLC on silica gel (methanol:dichloromethane=1:20) to provideInt-5f. ¹H NMR (400 MHz, methanol-d4) δ 8.18 (s, 1H), 7.49-7.50 (d, J=6Hz, 2H), 7.26-7.31 (m, 3H), 5.11-5.21 (m, 2H), 4.24-4.27 (d, J=11.2 Hz,1H), 4.10-4.16 (m, 1H), 3.95-4.01 (m, 1H), 3.74-3.78 (m, 2H), 3.59-3.63(m, 2H), 3.45-3.53 (m, 1H), 3.42-3.44 (m, 2H), 3.28 (s, 3H), 2.32-2.40(m, 2H), 1.83-1.86 (m, 2H). MS (ESI) m/z: 477.1, 479.1.

Step G—Synthesis of Intermediate Compound Int-5g-1 and Int-5g-2

A solution of Int-5f (60 mg, 0.126 mmol) in dimethylsulfoxide (1.5 mL)and methanol (4 mL) was treated with N,N-diisopropylethylamine (0.11 mL,0.628 mmol), (2,4-difluorophenyl)methanamine (180 mg, 1.26 mmol) andPd(Ph₃P)₄ (29.11 mg, 0.025 mmol). The mixture was allowed to stir at 90°C. for 16 hours under carbon monoxide (1 atm). The mixture was cooled toroom temperature extracted by ethyl acetate (6 mL×3), washed with HCl (3mL, 1M) and brine (5 mL), dried over anhydrous sodium sulfate, filtered,concentrated under reduced pressure. The crude product was purifiedusing preparative TLC on silica gel (methanol: dichloromethane=1:20) toprovide the crude racemate. MS (ESI) m/z: 568.1. Chiral resolution toprovide the separated enantiomers was accomplished with SFC (ChiralpakAD-H 250×4.6 mm I.D., 5 um; 4% ethanol (0.05% diethylamine) in SC—CO₂;2.35 mL/min; 220 nm) to provide earlier eluting Int-5g-1 ¹H NMR (400MHz, CDCl₃) δ 10.46-10.48 (m, 1H), 8.65 (s, 1H), 7.60-7.62 (d, J=7.2 Hz,2H), 7.30-7.37 (m, 4H), 6.79-6.85 (m, 2H), 5.29-5.32 (m, 2H), 4.63-4.64(d, J=5.6 Hz, 2H), 4.23-4.30 (m, 1H), 4.12-4.14 (d, J=10.8 Hz, 1H),4.03-4.09 (m, 1H), 3.80-3.83 (d, J=10.8 Hz, 1H), 3.51-3.67 (m, 4H),3.44-3.46 (m, 2H), 3.33 (s, 3H), 2.43-2.45 (m, 1H), 2.29-2.31 (m, 1H),1.88-1.91 (m, 2H); and later eluting Int-5g-2¹H NMR (400 MHz, CDCl₃) δ10.46-10.48 (m, 1H), 8.65 (s, 1H), 7.60-7.62 (d, J=7.2 Hz, 2H),7.30-7.37 (m, 4H), 6.79-6.85 (m, 2H), 5.29-5.32 (m, 2H), 4.63-4.64 (d,J=5.6 Hz, 2H), 4.23-4.30 (m, 1H), 4.12-4.14 (d, J=10.8 Hz, 1H),4.03-4.09 (m, 1H), 3.80-3.83 (d, J=10.8 Hz, 1H), 3.51-3.67 (m, 4H),3.44-3.46 (m, 2H), 3.33 (s, 3H), 2.43-2.45 (m, 1H), 2.29-2.31 (m, 1H),1.88-1.91 (m, 2H).

Step H—Synthesis of Compound 12 and 13

A solution of Int-5g-1 (10 mg, 0.018 mmol) in N,N-dimethylformamide (1.5mL) was treated with lithium chloride (0.747 mg, 0.018 mmol). Theresulting solution was heated to 85° C. for 1.5 hours, cooled to roomtemperature and directly purified using RP-HPLC to provide Compound 12.¹H NMR (400 MHz, CDCl₃) δ 12.83 (s, 1H), 10.40 (s, 1H), 8.52 (s, 1H),7.32-7.38 (m, 1H), 6.75-6.82 (m, 2H), 4.60-4.62 (d, J=5.2 Hz, 2H),4.02-4.18 (m, 3H), 3.80-3.82 (d, J=10.4 Hz, 1H), 3.67-3.70 (d, J=10.8Hz, 4H), 3.45-3.46 (d, J=5.2 Hz, 2H), 3.29 (s, 3H), 2.43-2.45 (m, 1H),2.25-2.27 (m, 1H), 1.89-1.92 (m, 2H). MS (ESI) m/z: 478.2. A similarprocedure was used to convert Int-5g-2 to Compound 13. ¹H NMR (400 MHz,CDCl₃) δ 12.86 (br s, 1H), 10.39 (br s, 1H), 8.53 (s, 1H), 7.33-7.45 (m,1H), 6.81 (q, J=9.5 Hz, 2H), 4.63 (d, J=4.7 Hz, 2H), 4.10-4.25 (m, 2H),4.00-4.09 (m, 1H), 3.83 (d, J=10.6 Hz, 1H), 3.74 (s, 2H), 3.69 (t, J=6.7Hz, 2H), 3.40-3.51 (m, 2H), 3.31 (s, 3H), 2.46 (td, J=6.7, 13.3 Hz, 1H),2.20-2.36 (m, 1H), 1.86-2.00 (m, 2H). MS (ESI) m/z: 478.1

The following compounds of the present invention were made using themethods described above in Example 5 and substituting the appropriatereactants and reagents:

Chiral resolution was accomplished after Step G in Example 5 with SFCaccording to the conditions shown as footnotes to the following table.

Compound Exact Mass Number Structure [M + H]⁺ 14^(a)

Calc'd 420.1, found 420.2 15^(a)

Calc'd 420.1, found 420.2 16^(b)

Calc'd 434.2, found 434.2 17^(b)

Calc'd 434.2, found 434.2 18^(c)

Calc'd 450.1, found 450.3 19^(c)

Calc'd 450.1, found 450.3 20^(d)

Calc'd 464.2, found 464.1 21^(d)

Calc'd 464.2, found 464.1 22^(e)

Calc'd 478.2, found 478.2 23^(e)

Calc'd 478.2, found 478.2 24

Calc'd 450.1, found 450.3 25^(f)

Calc'd 498.1, found 498.3 26^(f)

Calc'd 498.1, found 498.3 27^(f)

Calc'd 480.1, found 480.3 28^(f)

Calc'd 480.1, found 480.3 29^(f)

Calc'd 480.1, found 480.3 30^(f)

Calc'd 480.1, found 480.3 31

Calc'd 570.2, found 570.5 ^(a)Chiralcel AD 250 × 30 mm, 10 um, 50%ethanol (0.1% NH₃H₂O) in SC—CO₂, 80 mL/min, 220 nm ^(b)Chiralpak OJ 250× 30 mm, 5 um 20% ethanol (0.1% NH₃H₂O) in SC—CO₂, 60 mL/min, 220 nm^(c)Chiralcel AD 250 × 30 mm, 10 um, 35% 2-propanol (0.1% diethylamine)in SC—CO₂, 80 mL/min, 220 nm ^(d)Chiralpak AD 250 × 30 mm, 10 um, 30%2-propanol (0.1% NH₃H₂O) in SC—CO₂, 80 mL/min, 220 nm ^(e)Chiralpak AD250 × 30 mm, 10 um, 50% ethanol (0.1% NH₃H₂O) in SC—CO₂, 80 mL/min, 220nm ^(f)Chiralpak AD-H 250 × 30 mm, 40% iPrOH (0.1% diethylamine) inSC—CO₂, 80 mL/min, 220 nm

Example 6 Preparation of Compound 32

Step A—Synthesis of Compound 32

A solution of Compound 5-20 (15 mg, 0.023 mmol) in dichloromethane (1.0mL) under an atmosphere of nitrogen gas was treated withbromotrimethylsilane (17.4 mg, 0.114 mmol). The mixture was allowed tostir for 2 hours at room temperature, treated with additionalbromotrimethylsilane (17.4 mg, 0.114 mmol) and stirred for an additonal16 hours.

The sample was loaded onto a plug of silica gel, and the plug was rinsedwith 0.5% triethylamine in ethyl acetate followed by 1% HCl in ethylacetate/ACN (1:1 v/v). The filtrate was concentrated in vacuo andpurified using preparative RP-HPLC to provide Compound 32. MS (+ESI) m/z514.4

Example 7 Preparation of Compounds 33 and 34

Step A—Synthesis of Intermediate Compound Int-7a

A solution of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (1.50 g,6.10 mmol) in ethanol (80 mL) was treated with2-amino-2-(hydroxymethyl)propane-1,3-diol (5.90 g, 49 mmol) and themixture was allowed to stir at 100° C. for 72 hours, cooled to roomtemperature, filtered and concentrated in vacuo. The resulting residuewas purified using column chromatography on silica gel(dichloromethane:methanol=10:1) to provide Int-7a. ¹H NMR (400 MHz,DMSO-d₆) δ 7.80 (d, J=8.0 Hz, 1H), 7.47 (d, J=7.2 Hz, 2H), 7.27-7.35 (m,3H), 6.36 (d, J=8.0 Hz, 1H), 5.44 (t, J=4.8 Hz, 2H), 5.10 (s, 2H), 4.52(s, 2H), 3.77-3.81 (m, 2H), 3.32-3.69 (m, 2H). MS (+ESI) m/z: 332.2

Step B—Synthesis of Intermediate Compound Int-7b

A mixture of Int-7a (620 mg, 1.87 mmol) and Ph₃P (981 mg, 3.74 mmol) intoluene (30 mL) was purged with nitrogen and treated with DIAD (0.725mL, 3.7 mmol) via syringe. The resulting mixture was irradiated in amicrowave reactor at 140° C. for 45 minutes, concentrated in vacuo andthe crude residue was purified using column chromatography on silica gel(10:1 dichloromethane:methanol) to provide Int-7b. ¹H NMR (400 MHz,CDCl₃) δ 7.82 (d, J=8.0 Hz, 1H), 7.53 (d, J=6.4 Hz, 2H), 7.31-7.35 (m,3H), 6.58 (d, J=8.0 Hz, 1H), 5.36 (s, 2H), 4.91 (d, J=8.0 Hz, 2H), 4.70(d, J=8.0 Hz, 2H), 4.63 (s, 2H).

Step C—Synthesis of Intermediate Compound Int-7c

A solution of Int-7b (100 mg, 0.319 mmol) in THF (2.5 mL) and methanol(0.5 mL) was treated with ethanamine (70% in water) (576 mg, 12.77 mmol)and heated at 65° C. in sealed tube for 1 hour, cooled to roomtemperature and concentrated in vacuo to provide the Int-7c. ¹H NMR (400MHz, DMSO-d₆) δ 8.70-8.80 (m, 1H), 7.26-7.35 (m, 5H), 7.13 (d, J=8.0 Hz,1H), 6.24 (d, J=8.0 Hz, 1H), 5.48-5.52 (m, 1H), 5.02 (s, 2H), 4.84 (d,J=6.8 Hz, 2H), 4.28-4.32 (m, 2H), 4.04 (d, J=4.2 Hz, 2H), 3.05-3.15 (m,2H), 0.96 (t, J=7.2 Hz, 3H). MS (+ESI) m/z: 359.1.

Step D—Synthesis of Intermediate Compound Int-7d

A stirred solution of Int-7c (100 mg, 0.279 mmol) in 1,2-dichloroethane(5 mL) was treated with Dess-Martin periodinane (237 mg, 0.56 mmol). Thereaction mixture was allowed to stir at 18° C. for 16 hours, dilutedwith ethyl acetate (10 mL), filtered and concentrated in vacuo. Theresulting residue was purified using preparative TLC on silica gel(dichloromethane:methanol=20:1) to provide Int-7d. ¹H NMR (400 MHz,CDCl₃) δ 7.55 (d, J=6.8 Hz, 2H), 7.41 (d, J=8.0 Hz, 1H), 7.32-7.37 (m,3H), 6.42 (d, J=8.0 Hz, 1H), 4.92 (d, J=9.2 Hz, 1H), 4.79 (d, J=8.8 Hz,1H), 4.68 (d, J=8.8 Hz, 1H), 4.49-4.55 (m, 2H), 4.35 (d, J=8.0 Hz, 1H),3.83-3.88 (m, 1H), 3.48-3.51 (m, 2H), 1.32 (t, J=6.8 Hz, 3H). MS (+ESI)m/z: 357.1.

Step E—Synthesis of Intermediate Compound Int-7e

A solution of Int-7d (80 mg, 0.224 mmol) in dichloromethane (5 mL) wastreated with NBS (80 mg, 0.449 mmol) at 0° C., stirred for 6 hours at18° C. and then quenched with aqueous Na₂SO₃ (5 mL) and extracted withdichloromethane (10 mL×3). The combined organic layers were dried overanhydrous sodium sulfate and concentrated in vacuo. The resultingresidue was purified using preparative TLC on silica gel(dichloromethane:ethyl acetate=1:1) to provide Int-7e. ¹H NMR (400 MHz,CDCl₃) δ 7.62 (s, 1H), 7.52 (d, J=6.8 Hz, 2H), 7.28-7.38 (m, 3H), 5.28(m, 1H), 4.76-4.83 (m, 2H), 4.55 (d, J=9.2 Hz, 1H), 4.50 (d, J=8.0 Hz,1H), 4.30 (d, J=8.0 Hz, 1H), 4.14-4.29 (m, 1H), 3.68-3.78 (m, 2H), 1.39(t, J=7.2 Hz, 3H).

Step F—Synthesis of Intermediate Compound Int-7f

A solution of Int-7e (60 mg, 0.138 mmol) in N,N-dimethylformamide (6 mL)at 0° C. was treated with NaH (22.05 mg, 0.55 mmol) and iodomethane(0.086 mL, 1.38 mmol). The reaction mixture was allowed to stir for 10minutes at 18° C., quenched with water (10 mL) and extracted withdichloromethane (10 mL×3). The combined organic layers were dried overanhydrous sodium sulfate and concentrated in vacuo. The resultingresidue was purified using preparative TLC in silica gel(dichloromethane:methanol=20:1) to provide Int-7f. ¹H NMR (400 MHz,CDCl₃) δ 8.16 (s, 1H), 7.64 (d, J=7.2 Hz, 2H), 7.28-7.35 (m, 3H), 5.51(d, J=10.0 Hz, 1H), 5.21 (d, J=8.8 Hz, 1H), 5.08 (d, J=10.0 Hz, 1H),5.03 (s, 1H), 4.78 (d, J=8.8 Hz, 1H), 4.58-4.64 (m, 2H), 4.17-4.22 (m,1H), 3.34 (s, 3H), 3.19-3.26 (m, 1H), 1.31 (t, J=7.2 Hz, 3H). MS (+ESI)m/z: 449.1, 451.1.

Step G—Synthesis of Intermediate Compound Int-7g-1 and Int-7g-2

A mixture of Int-7f (40 mg, 0.089 mmol), N,N-diisopropylethylamine(0.047 mL, 0.267 mmol) and (2,4-difluorophenyl)methanamine (63.7 mg,0.445 mmol) in dimethylsulfoxide (1 mL) and methanol (4 mL) was treatedwith Pd(Ph₃P)₄ (51.4 mg, 0.045 mmol) under nitrogen. The mixture wasallowed to stir at 80° C. for 3 hours under carbon monoxide (1 atm) andthen concentrated in vacuo. The resulting residue was dissolved in ethylacetate (10 mL), filtered and the filtrate was washed with 1N HCl (10mL), dried over anhydrous sodium sulfate and concentrated in vacuo. Theresulting residue was purified using preparative TLC on silica gel(ethyl acetate: dichloromethane=1.5:1) to provide the product racemate.Chiral resolution to provide the enantiomers was accomplished with SFC(Chiral Pak OJ, 5 μm, 250×30 mm, 75:25 SC—CO₂:methanol (with 0.1%NH₃H₂O), 60 mL/min, 220 nm) to provide earlier eluting Int-7g-1 ¹H NMR(400 MHz, CDCl₃) δ 10.39 (s, 1H), 8.88 (s, 1H), 7.59 (d, J=6.8 Hz, 2H),7.28-7.38 (m, 4H), 6.79-6.83 (m, 2H), 5.41-5.45 (m, 2H), 5.11 (d, J=10.0Hz, 1H), 5.05 (s, 1H), 4.69 (d, J=8.8 Hz, 1H), 4.56-4.63 (m, 4H),4.15-4.19 (m, 1H), 3.34 (s, 3H), 3.21-3.27 (m, 1H), 1.31 (t, J=7.2 Hz,3H). MS (M+H)⁺540.2 and later eluting Int-7g-2 ¹H NMR (400 MHz, CDCl₃) δ10.35 (s, 1H), 8.84 (s, 1H), 7.54 (d, J=6.8 Hz, 2H), 7.23-7.33 (m, 4H),6.72-6.77 (m, 2H), 5.41-5.45 (m, 2H), 5.11 (d, J=10.0 Hz, 1H), 5.05 (s,1H), 4.69 (d, J=8.8 Hz, 1H), 4.56-4.63 (m, 4H), 4.15-4.19 (m, 1H), 3.34(s, 3H), 3.21-3.27 (m, 1H), 1.31 (t, J=7.2 Hz, 3H). MS (+ESI) m/z: 540.2

Step H—Synthesis of Compound 33

A solution of Int-7g-1 (15 mg, 0.027 mmol) and lithium chloride (12 mg,0.278 mmol) in N,N-dimethylformamide (2 mL) was allowed to stir at 100°C. for 1 hour. The mixture was directly purified using RP-HPLC toprovide Compound 33. ¹H NMR (400 MHz, CDCl₃) δ 10.42 (s, 1H), 8.87 (s,1H), 7.34-7.40 (m, 1H), 6.78-6.85 (m, 2H), 5.53 (d, J=8.8 Hz, 1H), 5.22(s, 1H), 4.75 (d, J=8.8 Hz, 1H), 4.65 (d, J=5.6 Hz, 2H), 4.51-4.56 (m,2H), 4.32-4.34 (m, 1H), 3.52 (s, 3H), 3.26-3.31 (m, 1H), 1.36 (t, J=7.2Hz, 3H). MS (M+H)⁻: 450.1.

Step I—Synthesis of Compound 34

A solution of Int-7g-2 (15 mg, 0.027 mmol) and lithium chloride (12 mg,0.278 mmol) in N,N-dimethylformamide (2 mL) was allowed to stir at 100°C. for 1 hour. The mixture was directly purified using RP-HPLC toprovide Compound 34. ¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 8.87 (s,1H), 7.34-7.40 (m, 1H), 6.78-6.85 (m, 2H), 5.53 (d, J=8.8 Hz, 1H), 5.22(s, 1H), 4.75 (d, J=8.8 Hz, 1H), 4.65 (d, J=5.6 Hz, 2H), 4.51-4.56 (m,2H), 4.32-4.34 (m, 1H), 3.52 (s, 3H), 3.26-3.31 (m, 1H), 1.36 (t, J=7.2Hz, 3H). MS (+ESI) m/z: 450.1.

Example 8 Preparation of Compounds 35-37

Step A—Synthesis of Intermediate Compound Int-8a

To a flame-dried flask under an atmosphere of nitrogen,3-((tert-butoxycarbonyl)amino)tetrahydrofuran-3-carboxylic acid (5.0 g,21.6 mmol) was dissolved in anhydrous THF (100 mL). This solution wascooled in an ice bath and LiAlH₄ (2M in THF, 22.7 mL, 45.4 mmol) wasadded dropwise to the stirred mixture at 0° C. The ice bath was removedand the reaction was allowed to stir at room temperature for 5 hours.The reaction was cooled in an ice bath and quenched with acetone (2 mL).After 10 minutes of stirring, it was treated sequentially with water(1.72 mL), 15% aq. NaOH (1.72 mL), followed by water (5.16 mL). Themixture was allowed to stir at room temperatureovernight. The solidswere filtered away and rinsed with ethyl acetate. The filtrate waswashed with brine (3×), dried over anhydrous sodium sulfate, filtered,and the filtrate was concentrated in vacuo to provide Int-8a. ^(H)NMR(500 MHz, CDCl₃) δ 4.92 (s, 1H), 3.98-3.88 (m, 2H), 3.85-3.75 (m, 4H),2.11-2.03 (m, 2H), 1.44 (s, 9H). MS (+ESI) m/z: 218.3.

Step B—Synthesis of Intermediate Compound Int-8b

A solution of Int-8a (860 mg, 3.96 mmol) and3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (750 mg, 3.05 mmol) andN,N-diisopropylethylamine (0.85 mL, 4.87 mmol) in dichloromethane (20mL) was treated with HATU (1.27 g, 3.35 mmol). The mixture was allowedto stir at room temperature for 5 hours. The reaction was diluted withaqueous HCl and extracted with dichloromethane (3×). The combinedorganics were washed with aqueous sodium bicarbonate (1×), dried oversodium sulfate, filtered, and the filtrate was concentrated in vacuo.The resulting residue was purified using gradient elution on silica gel(50% to 100% ethyl acetate in hexanes) to provide Int-8b. MS (+ESI) m/z:446.2.

Step C—Synthesis of Intermediate Compound Int-8c

To a solution of Int-8b (1.20 g, 2.69 mmol) in dichloromethane (40 mL)was added trifluoroacetic acid portionwise (6 mL). The mixture wasallowed to stir at room temperature for 4 hours and then concentrated invacuo. The resulting residue was dissolved in

EtOH and then concentrated in vacuo. The resulting residue was dissolvedin EtOH (200 mL) and heated at 60° C. for 16 hours, 80° C. for 24 hoursand then 60° C. for an additional 18 hours. The reaction wasconcentrated in vacuo and the resulting residue was purified usingRP-HPLC to provide Int-8c. ¹H NMR (500 MHz, CDCl₃) δ 7.58-7.54 (m, 3H),7.37-7.29 (m, 3H), 6.55 (d, J=7.8 Hz, 1H), 5.49 (d, J=10.5 Hz, 1H), 5.35(d, J=10.3 Hz, 1H), 4.38 (d, J=12.0 Hz, 1H), 4.29 (d, J=12.0 Hz, 1H),4.22-4.16 (m, 2H), 4.06-4.01 (m, 1H), 3.75 (d, J=11.0 Hz, 1H), 2.50-2.42(m, 1H), 2.36-2.28 (m, 1H). MS (+ESI) m/z: 328.3.

Step D—Synthesis of Intermediate Compound Int-8d

To a solution of Int-8c (100 mg, 0.31 mmol) in dichloromethane (20 mL)was added ethylamine (70% in water, 1 mL, 12.6 mmol). The vessel wassealed and heated at 65° C. for 2 hours and then concentrated in vacuo.The resulting residue was dissolved in 1:1 acetonitrile and toluene andthen concentrated in vacuo to provide Int-8d that was used withoutfurther purification. MS (+ESI) m/z: 373.4.

Step E—Synthesis of Intermediate Compound Int-8e

To a solution of Int-8d (100 mg, 0.27 mmol) in dichloromethane (20 mL)was added Dess-Martin periodinane (159 mg, 0.38 mmol) and allowed tostir at room temperature for 90 minutes. The reaction was diluted withaqueous sodium bicarbonate, stirred for 20 minutes and then extractedwith dichloromethane (4×). The combined organic layers were dried oversodium sulfate, filtered, and concentrated in vacuo. The resultingresidue was dissolved in a 1:1 mixture of acetonitrile and toluene andthen concentrated in vacuo to provide Int-8e which was used withoutfurther purification. MS (+ESI) m/z: 371.4.

Step F—Synthesis of Intermediate Compound Int-8f

A solution of Int-8e (107 mg, 0.29 mmol) in anhydrousN,N-dimethylformamide (15 mL), under an atmosphere of nitrogen, wastreated with sodium hydride (29 mg, 1.16 mmol). The reaction was allowedto stir for 5 minutes at room temperature and then methyl iodide (90 uL,1.44 mmol) was added. After 30 minutes, the reaction was recharged withsodium hydride (10 mg, 0.42 mmol) and methyl iodide (200 uL, 3.20 mmol).After 30 minutes, the reaction was recharged again with sodium hydride(5 mg, 0.21 mmol) and methyl iodide (100 uL, 1.60 mmol). After 20minutes, the reaction was cooled in an ice bath, neutralized withaqueous HCl (1N), diluted with brine, and extracted with dichloromethane(4×). The combined organics were dried over sodium sulfate, filtered,and the filtrate was concentrated in vacuo to provide Int-8f which wasused without further purification. MS (+ESI) m/z: 385.3.

Step G—Synthesis of Intermediate Compound Int-8g

To a mixture of Int-8f (100 mg, 0.26 mmol) in dichloromethane (10 mL)was added NBS (69 mg, 0.39 mmol). The reaction was allowed to stir atroom temperaturein the dark, periodically recharged three times with NBS(25 mg, 0.14 mmol). After 6 hours total, the reaction was diluted withaqueous sodium carbonate (2M) and extracted with dichloromethane (3×).The combined organics layers were dried over sodium sulfate, filtered,and concentrated in vacuo. The resulting residue was purified usingcolumn chromatography on silica gel (0-5% MeOH in ethyl acetate) toprovide Int-8g. MS (+ESI) m/z: 463.2, 465.2.

Step H—Synthesis of Intermediate Compounds Int-8h-1, Int-8h-2, andInt-8h-3

To a solution of Int-8g (33 mg, 0.071 mmol) in N,N-dimethylformamide (1mL) was added N-cyclohexyl-N-methylcyclohexanamine (0.05 mL, 0.24 mmol)and (2,4-difluorophenyl) methanamine (60 mg, 0.42 mmol). A stream of CO(g) was bubbled through the solution,bis(tri-t-butylphosphine)palladium(0) (36 mg, 0.071 mmol) was added. Thereaction was heated at 90° C. for 3 hours under CO (1 atm). The reactionwas filtered, washed with dichloromethane, diluted with aqueous HCl, andextracted with dichloromethane (3×). The combined organic layers weredried over anhydrous sodium sulfate, filtered, and the filtrate wasconcentrated in vacuo. The resulting residue was purified using gradientelution on silica gel (40-100% ethyl acetate in hexane) to provide theearlier eluting diastereomer A and the later eluting diastereomer B asInt-8h-1 (diastereomer B). The enantiomers of diastereomer A wereseparated using chiral preparative SFC (2×25 cm Chiralpak AS, 25% iPrOHwith 0.1% DEA modifier/75% CO₂, 50 mL/min, 220 nM) to provide earliereluting Int-8h-2 (diastereomer A, enantiomer A) and later elutingInt-8h-3 (diastereomer A, enantiomer B). Int-8h-1 (diastereomer B):¹HNMR (500 MHz, CDCl₃) δ 10.47 (t, J=5.9 Hz, 1H), 8.47 (s, 1H), 7.63 (d,J=6.8 Hz, 2H), 7.46-7.29 (m, 4H), 6.85-6.78 (m, 2H), 5.46 (d, J=10.0 Hz,1H), 5.15 (d, J=10.0 Hz, 1H), 4.67 (dd, J=15.1, 5.9 Hz, 1H), 4.59 (dd,J=15.1, 5.9 Hz, 1H), 4.46 (s, 1H), 4.36-4.31 (m, 1H), 4.21-4.13 (m, 2H),3.83 (d, J=10.0 Hz, 1H), 3.74 (d, J=9.8 Hz, 1H), 3.32 (s, 3H), 3.22-3.14(m, 1H), 2.78-2.71 (m, 1H), 2.49-2.42 (m, 1H), 1.29 (t, J=7.1 Hz, 3H).MS (+ESI) m/z: 554.2. Int-8h-2/ Int-8h-3 (diastereomer A): ¹H NMR (500MHz, CDCl₃) δ 10.47 (t, J=5.9 Hz, 1H), 8.76 (s, 1H), 7.63 (d, J=6.8 Hz,2H), 7.42-7.28 (m, 4H), 6.85-6.77 (m, 2H), 5.47 (d, J=10.0 Hz, 1H), 5.15(d, J=10.0 Hz, 1H), 4.67 (dd, J=15.1, 6.1 Hz, 1H), 4.58 (dd, J=15.1, 6.1Hz, 1H), 4.48 (d, J=12.2 Hz, 1H), 4.42 (s, 1H), 4.22-4.15 (m, 2H),4.09-4.04 (m, 1H), 3.86 (d, J=12.2 Hz, 1H), 3.27 (s, 3H), 3.26-3.18 (m,1H), 2.34-2.27 (m, 1H), 2.13-2.07 (m, 1H), 1.33 (t, J=7.1 Hz, 3H), MS(+ESI) m/z: 554.3.

Step I—Synthesis of Compound 35

To a solution of Int-8h-1 (diastereomer B) (7.7 mg, 0.014 mmol) inN,N-dimethylformamide (1.2 mL) was added lithium chloride (11 mg, 0.26mmol) and the reaction was heated at 100° C. for 5 hours. The reactionwas diluted with water and directly purified using RP-HPLC to provideCompound 35. ¹H NMR (499 MHz, DMSO-d₆): δ 12.46 (s, 1H), 10.27 (t, J=5.9Hz, 1H), 8.20 (s, 1H), 7.43-7.38 (m, 1H), 7.26-7.21 (m, 1H), 7.08-7.04(m, 1H), 5.28 (s, 1H), 4.54 (d J=5.9 Hz, 2H), 4.13-4.06 (m, 2H),4.04-3.97 (m, 1H), 3.79 (d, J=9.8 Hz, 1H), 3.71 (d, J=9.8 Hz, 1H), 3.44(s, 3H), 3.33-3.25 (m, 1H), 2.71-2.60 (m, 2H), 1.20 (t, J=7.1 Hz, 3H).MS (+ESI) m/z: 464.2.

Step J—Synthesis of Compound 36 and 37

To a degassed solution of Int-8h-3 (diastereomer A, enantiomer 2) (8 mg,0.014 mmol) in methanol (5 mL) was added 10% Pd on carbon (8 mg) Thereaction was stirred under hydrogen (1 atm) for an hour at roomtemperature, filtered, and the filtrate was concentrated in vacuo. Theresulting residue was purified using RP-HPLC to provide Compound 36. ¹HNMR (499 MHz, DMSO-d₆): δ 12.29 (s, 1H), 10.30 (t, J=5.9 Hz, 1H), 8.47(s, 1H), 7.43-7.38 (m, 1H), 7.26-7.21 (m, 1H), 7.08-7.04 (m, 1H), 5.26(s, 1H), 4.53 (d J=5.9 Hz, 2H), 4.43 (d, J=11.7 Hz, 1H), 4.18-4.11 (m,1H), 4.00-3.91 (m, 3H), 3.38 (s, 3H), 3.33-3.25 (m, 1H), 2.38-2.32 (m,1H), 2.13-2.08 (m, 1H), 1.25 (t, J=7.0 Hz, 3H). MS (+ESI) m/z: 464.2. Asimilar procedure was used to convert Int-8h-2 to Compound 37. MS (+ESI)m/z: 464.2.

Example 9 Preparation of Compound 38

Step A—Synthesis of Intermediate Compound Int-9a

A solution of 1,1-dimethylhydrazine (178 mg, 2.97 mmol) in CH₂Cl₂ (10mL) under an atmosphere of nitrogen gas was treated withtrimethylaluminum (1.48 mL, 2.97 mmol). The mixture was allowed to stirat 18° C. for 20 minutes and was then treated with a solution of Int-7b(310 mg, 1 mmol) in dichloromethane (5 mL). The mixture was allowed tostir at 18° C. for 16 hours, quenched with water (5 drops), diluted withdichloromethane (10 mL) and filtered. The filtrate was dried overanhydrous sodium sulfate and concentrated in vacuo. The crude residuewas purified using preparative TLC on silica gel(dichloromethane:methanol=10:1) to provide Int-9a. ¹H NMR (400 MHz,CDCl₃) δ 7.30-7.35 (m, 2H), 7.24-7.28 (m, 3H), 6.90 (d, J=8.0 Hz, 1H),6.24 (d, J=8.0 Hz, 1H), 4.92-4.98 (m, 4H), 4.46 (d, J=4.4 Hz, 2H), 4.32(s, 2H), 2.40 (s, 6H).

Step B—Synthesis of Intermediate Compound Int-9b

A solution of Int-9a in dichloromethane (10 mL) was treated withdimethylsulfoxide (0.51 mL, 7.14 mmol), N,N-diisopropylethylamine (0.84mL, 4.64 mmol) and PySO₃ (682 mg, 4.29 mmol) at 5° C. The mixture wasallowed to stir at 25° C. for 16 hours and then concentrated in vacuo.The resulting residue was purified using preparative TLC on silica gel(dichloromethane:methanol=10:1) to provide Int-9b. ¹H NMR (400 MHz,CDCl₃) δ 7.50-7.56 (m, 2H), 7.42 (d, J=7.2 Hz, 1H), 7.25-7.31 (m, 3H),6.44 (d, J=8.0 Hz, 1H), 5.51 (s, 1H), 5.04 (d, J=10.0 Hz, 1H), 4.86 (d,J=9.2 Hz, 1H), 4.72 (d, J=9.2 Hz, 1H), 4.54-4.57 (m, 2H), 4.38 (d, J=6.8Hz, 1H), 2.96 (s, 6H). MS (+ESI) m/z: 372.1

Step C—Synthesis of Intermediate Compound Int-9c

A solution of Int-9b (60 mg, 0.16 mmol) in dichloromethane (8 mL) wastreated with N-bromosuccinimide (57.6 mg, 0.32 mmol) at 0° C. Themixture was allowed to stir at 25° C. for 2 hours, concentrated in vacuoand the resulting residue was purified using preparative TLC on silicagel (dichloromethane:methanol=10:1) to provide Int-9c. ¹H NMR (400 MHz,CDCl₃) δ 7.78 (s, 1H), 7.53 (d, J=6.8 Hz, 2H), 7.30-7.36 (m, 3H), 5.44(s, 1H), 5.02 (d, J=9.2 Hz, 1H), 4.87 (d, J=8.8 Hz, 1H), 4.55-4.64 (m,3H), 4.39 (d, J=7.2 Hz, 1H), 2.98 (s, 6H). MS (+ESI) m/z: 448.1, 450.1

Step D—Synthesis of Intermediate Compound Int-9d

A solution of Int-9c (40 mg, 0.088 mmol) in N,N-dimethylformamide (3 mL)at 0° C. was treated with NaH (10.7 mg, 0.27 mmol) and iodomethane (0.05mL, 0.888 mmol). The reaction mixture was allowed to stir at 25° C. for1 hour, quenched with water (10 mL) and the mixture was extracted withdichloromethane (10 mL×4). The combined organic layers were dried overanhydrous sodium sulfate, concentrated in vacuo and the resultingresidue was purified using preparative TLC on silica gel(dichloromethane:ethyl acetate=1:1) to provide Int-9d. ¹H NMR (400 MHz,CDCl₃) δ 8.04 (s, 1H), 7.50 (d, J=6.4 Hz, 2H), 7.22-7.28 (m, 3H), 5.45(d, J=6.4 Hz, 1H), 5.06-5.13 (m, 2H), 5.03 (s, 1H), 4.69 (d, J=8.8 Hz,1H), 4.62 (d, J=8.0 Hz, 1H), 4.51 (d, J=6.8 Hz, 1H), 3.40 (s, 3H), 2.90(s, 6H). MS (+ESI) m/z: 464.0, 466.0

Step E—Synthesis of Intermediate Compound Int-9e

A mixture of Int-9d (10 mg, 0.022 mmol), N,N-diisopropylethylamine(0.011 mL, 0.065 mmol) and (2,4-difluorophenyl)methanamine (15.4 mg,0.11 mmol) in dimethylsulfoxide (1 mL) and methanol (4 mL) was addedPd(Ph₃P)₄ (12.4 mg, 10.8 μmol) under N₂. The mixture was allowed to stirat 90° C. for 2 hours under carbon monoxide (1 atm) cooled to roomtemperature and concentrated in vacuo. The resulting residue wasdissolved in ethyl acetate, filtered and concentrated in vacuo. Theresulting residue was purified using preparative TLC on silica gel(ethyl acetate:petroleum ether=1.5:1) to provide Int-9e. ¹H NMR (400MHz, CDCl₃) δ 10.33 (s, 1H), 8.77 (s, 1H), 7.46 (d, J=6.8 Hz, 2H),7.11-7.31 (m, 4H), 6.73-6.78 (m, 2H), 5.33-5.41 (m, 2H), 5.06-5.12 (m,2H), 4.50-4.63 (m, 5H), 3.61 (s, 3H), 2.90 (s, 6H). MS (+ESI) m/z: 555.2

Step F—Synthesis of Compound 38

A solution of Int-9e (5 mg, 9 μmol) and lithium chloride (0.4 mg, 9μmol) in N,N-dimethylformamide (2 mL) was allowed to stir at 100° C. for1 hour, cooled to room temperature and concentrated in vacuo. Theresulting residue was purified using RP-HPLC to provide Compound 38. ¹HNMR (400 MHz, CDCl₃) δ 10.31 (s, 1H), 8.79 (s, 1H), 7.33-7.37 (m, 1H),6.78-6.82 (m, 2H), 5.48 (d, J=8.8 Hz, 1H), 5.26 (s, 1H), 4.70 (d, J=8.0Hz, 1H), 4.64 (d, J=6.0 Hz, 2H), 4.56 (d, J=6.8 Hz, 1H), 4.44 (d, J=7.2Hz, 1H), 3.71 (s, 3H), 3.02 (s, 6H). MS (+ESI) m/z: 465.1

Example 10 Preparation of Compounds 39 and 40

Step A—Synthesis of Intermediate Compound Int-10a

A solution of (±)-Int-5e (1.00 g, 2.47 mmol) in N,N-dimethylformamideunder nitrogen at 0° C. was treated with a solution of LiHMDS (1M inTHF, 2.71 mL, 2.71 mmol). The mixture was allowed to stir at 0° C. for20 minutes and was then treated with 1-bromo-2-methoxyethane (0.371 mL,3.95 mmol). The mixture was allowed to stir at room temperature for 16hours, treated with 1N aqueous HCl until pH 3 and extracted withdichloromethane. The combined organic layers were dried over anhydroussodium sulfate, filtered and concentrated in vacuo. The resultingresidue was purified using column chromatography on silica gel (0-5%methanol/ ethyl acetate) to provide Int-10a. MS (+ESI) m/z: 463.3,465.3.

Step B—Synthesis of Intermediate Compound Int-10b

A solution of Int-10a (315 mg, 0.680 mmol), butan-1-ol (0.622 ml, 6.80mmol) and N-cyclohexyl-N-methylcyclohexanamine (0.288 ml, 1.36 mmol) inN,N-dimethylformamide (6.80 mL) was sub-surface sparged with nitrogengas for 3 minutes, treated with bis(tri-t-butylphosphine)palladium(0)(174 mg, 0.340 mmol) and sparging was continued for 1 minute The flaskwas sealed with a rubber septum, evacuated and backfilled with carbonmonoxide. The mixture was stirred under carbon monoxide (1 atm) at 90°C. for 5.5 hours. The mixture was cooled to room temperature, filteredand the filtrate was directly purified using RP-HPLC to provide Int-10b.MS (+ESI) m/z: 485.4.

Step C—Synthesis of Intermediate Compound Int-10c

A solution of Int-10b (150 mg, 0.310 mmol) in THF (2 mL), methanol (0.5mL), water (0.5 mL) was treated with lithium hydroxide hydrate (65.0 mg,1.548 mmol) and allowed to stir at 40° C. for 40 minutes. The mixturewas concentrated in vacuo and azeotropically dried with acetonitrile toprovide Int-10c that was used without further purification. MS (+ESI)m/z: 429.3.

Step D—Synthesis of Intermediate Compound Int-10d

A mixture of Int-10c (133 mg, 0.310 mmol),2-(2,4-difluorophenyl)acetohydrazide 2,2,2-trifluoroacetate (103 mg,0.341 mmol) and HATU (130 mg, 0.341 mmol) in N,N-dimethylformamide (1.55mL) was treated at room temperature with DIPEA (0.163 ml, 0.931 mmol).The mixture was allowed to stir for 10 minutes at room temperature andwas then directly purified using RP-HPLC to provide Int-10d. MS (+ESI)m/z: 597.4.

Step E—Synthesis of Intermediate Compound Int-10e-1 and IntermediateCompound Int-10e-2

A solution of Int-10d (69.3 mg, 0.116 mmol) in THF (1.16 mL) was treatedwith Lawesson's reagent (56.4 mg, 0.139 mmol) and allowed to stir at 60°C. for 16 hours. The mixture was concentrated in vacuo and the resultingresidue was purified using column chromatography on silica gel (0-5%MeOH in dichloromethane) to provide the product as the racemate.Separation of the enantiomers by chiral SFC (Chiralcel OJ-H; 30%isopropanol with 0.1% diethylamine in SC—CO₂; 80 mL/min; 254 nm)provided the earlier eluting Int-10e-1 (ent A) and the later elutingInt-10e-2 (ent B). MS (+ESI) m/z: 595.4.

Step E—Synthesis of Compound 39

A solution of Int-10e-1 (15 mg, 0.025 mmol) in dichloromethane (0.20 mL)was treated with trifluoroacetic acid (0.194 mL) and allowed to stir atroom temperature for 25 minutes. The mixture was concentrated in vacuoand the resulting residue was purified using RP-HPLC to provide Compound39. MS (+ESI) m/z: 505.3. ¹H NMR (500 MHz, CDCl₃): δ 8.78 (1H, s), 7.37(1H, q, J=7.5 Hz), 6.85-6.90 (2H, m), 4.51 (2H, s), 4.31 (1H, d, J=10.9Hz), 4.26 (1H, q, J=8.2 Hz), 4.09 (1H, q, J=7.5 Hz), 4.01 (1H, d, J=13.3Hz), 3.91 (2H, t, J=12.4 Hz), 3.78-3.81 (2H, m), 3.69-3.71 (2H, m), 3.41(3H, s), 2.43-2.49 (2H, m).

Step F—Synthesis of Compound 40

A solution of Int-10e-2 (12.1 mg, 0.020 mmol) in dichloromethane (0.157mL) was treated with trifluoroacetic acid (0.157 mL) and allowed to stirat room temperature for 25 minutes. The mixture was concentrated invacuo and the resulting residue was purified using RP-HPLC to provideCompound 40. MS (+ESI) m/z: 505.3. ¹H NMR (500 MHz, CDCl₃): δ 8.78 (1H,s), 7.35-7.40 (1H, m), 6.86-6.91 (2H, m), 4.53 (2H, s), 4.33 (1H, d,J=11.1 Hz), 4.24-4.29 (1H, m), 4.06-4.11 (1H, m), 4.02 (1H, d, J=13.4Hz), 3.91 (2H, t, J=12.6 Hz), 3.81 (2H, q, J=4.7 Hz), 3.69-3.71 (2H, m),3.41 (3H, s), 2.45-2.48 (2H, m).

Example 11 Preparation of Intermediate Compounds 41 and 42

Step A—Synthesis of Intermediate Compound Int-11a

A solution of compound tert-butyl 3-oxopyrrolidine-1-carboxylate (500mg, 2.70 mmol) and ammonia in THF (2M, 3 mL) was stirred at 28° C. for 2h, treated with trimethylsilanecarbonitrile (281 mg, 2.83 mmol) andstirred at 28° C. for 12 h. The mixture was concentrated to afford crudeInt-11a which was used directly in the next step without furtherpurification.

Step B—Synthesis of Intermediate Compound Int-11b

To a solution of compound Int-11a (500 mg, 2.367 mmol) and pyridine(1872 mg, 23.67 mmol) in tetrahydrofuran (10 mL) was added2,2,2-trifluoroacetic anhydride (597 mg, 2.84 mmol) at 0° C. The mixturewas stirred at 28° C. for 3 h, concentrated and the residue was purifiedby column chromatography on silica gel (25% to 50% ethyl acetate inpetroleum ether) to afford Int-11b: ¹H NMR (400 MHz, CDCl₃) δ 3.92-4.05(m, 1H), 3.76-3.89 (m, 1H), 3.39-3.71 (m, 2H), 2.45-2.72 (m, 2H), 1.46(s, 9H).

Step C—Synthesis of Intermediate Compound Int-11c

To a solution of compound Int-11b (400mg, 1.302 mmol) in ethanol (10 mL)was added Raney nickel (76 mg, 1.302 mmol) and the mixture was stirredunder hydrogen (1 atm) at 28° C. for 2 h. The mixture was filtered andthe filtrate was concentrated to afford crude Int-11c which was useddirectly in next step without further purification.

Step D—Synthesis of Intermediate Compound Int-11d

To a solution of compound Int-11c (100 mg, 0.321 mmol) in methanol (15mL) was added an aqueous solution of KOH (2.8 mL, 14.00 mmol) at 25° C.The mixture was stirred at 80° C. for 5 h and then concentrated. Theresidue was dissolved in dichloromethane (20 mL), filtered and thefiltrate was concentrated to afford crude Int-11d which was used in thenext step without further purification. ¹H NMR (400 MHz, CDCl₃) δ3.34-3.54 (m, 2H), 3.07-3.31 (m, 2H), 2.68 (s, 2H), 2.57-2.79 (m, 1H),1.74-1.86 (m, 1H), 1.58-1.70 (m, 1H), 1.43 (s, 9H).

Step E—Synthesis of Intermediate Compound Int-11e

To a solution of 3-(benzyloxy)-4-oxo-4H-pyran-2-carboxylic acid (1 g,4.06 mmol) in N,N-dimethylformamide (20 mL) was added Int-11d (1.312 g,6.09 mmol), N,N-diisopropylethylamine (2.128 mL, 12.18 mmol) and7-azabenzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate (AOP) (2.160 g, 4.87 mmol) at 0° C. The mixture wasstirred at 0° C. for 20 minutes, treated with water (50 mL) andextracted with ethyl acetate (50 mL×3). The organic phase was dried overanhydrous Na₂SO₄, filtered and the filtrate was concentrated. Theresidue was purified by preparative TLC on silica gel (5% methanol indichloromethane) to afford Int-11e. ¹H NMR (400 MHz, CDCl₃) 8.32 (s,1H), 7.63-7.76 (m, 1H), 7.32 (s, 5H), 6.26-6.43 (m, 1H), 5.37 (s, 2H),3.27-3.53 (m, 6H), 1.97-2.06 (m, 1H), 1.88 (s, 1H), 1.42 (s, 9H). MS(+ESI) m/z: 444.2.

Step F—Synthesis of Intermediate Compound Int-11f

To a solution of Int-11e (1 g, 2.255 mmol) in ethanol (80 mL) was addedtrifluoroacetic acid (0.035 mL, 0.451 mmol). The mixture was stirred at80° C. for 3 days and then concentrated.

The residue was purified by column chromatography on silica gel (5%methanol in dichloromethane). Further purification by preparative TLC onsilica gel (7% methanol in dichloromethane) afforded Int-11f. ¹H NMR(400 MHz, CDCl₃) δ 7.73 (s, 1H), 7.52 (d, J=7.2 Hz, 2H), 7.16-7.29 (m,4H), 6.43 (d, J=8.0 Hz, 1H), 5.27 (d, J=10.0 Hz, 1H), 5.13 (d, J=10.0Hz, 1H), 3.51-3.72 (m, 2H), 3.27-3.40 (m, 3H), 3.10 (s, 1H), 2.17 (dd,J=6.4, 13.0 Hz, 1H), 1.95 (s, 1H), 1.32-1.50 (m, 9H). MS (+ESI) m/z:426.2.

Step G—Synthesis of Intermediate Compound Int-11g

A solution of Int-11f (130 mg, 0.306 mmol) in dichloromethane (3 mL) wastreated with NBS (109 mg, 0.611 mmol) at 0° C. The mixture was stirredat 25° C. for 3 hours, quenched with aqueous Na₂SO₃ (3 mL) and extractedwith dichloromethane (10 mL×3). The combined organic portions were driedover Na₂SO₄, filtered and the filtrate was concentrated. The residue waspurified by preparative TLC on silica gel (7% methanol indichloromethane) to give Int-11g. ¹H NMR (400 MHz, CDCl₃) δ 7.56-7.60(m, 2H), 7.22-7.37 (m, 3H), 5.21-5.30 (m, 1H), 5.12 (d, J=9.6 Hz, 1H),3.79 (d, J=12.8 Hz, 1H), 3.34-3.65 (m, 5H), 3.13-3.22 (m, 1H), 2.19-2.28(m, 1H), 1.98-2.08 (m, 1H), 1.43-1.57 (m, 9H). MS (+ESI) m/z: 504.1.

Step H—Synthesis of Intermediate Compound Int-11h

A solution of Int-11g (200 mg, 0.397 mmol) in tetrahydrofuran (4 mL) wastreated with a solution of LiHMDS in tetrahydrofuran (1M, 0.595 mL,0.595 mmol) at -78° C. under nitrogen. The mixture was stirred at −78°C. for 30 minutes, treated with MeI (0.037 mL, 0.595 mmol), stirred at0° C. for 1.5 hours and then quenched with water (10 mL). The mixturewas extracted with ethyl acetate (10 mL×3) and the organic phase wasdried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated.The residue was purified by preparative TLC on silica gel (50% ethylacetate in dichloromethane) to afford Int-11h. ¹H NMR (400 MHz, CDCl₃) δ7.64 (d, J=7.2 Hz, 2H), 7.54 (s, 1H), 7.27-7.39 (m, 3H), 5.21 (d, J=7.6Hz, 1H), 5.08-5.15 (m, 1H), 3.87 (d, J=13.2 Hz, 1H), 3.59-3.67 (m, 1H),3.44-3.52 (m, 3H), 3.29 (d, J=6.4 Hz, 1H), 2.71-2.95 (m, 3H), 2.29 (s,1H), 2.11 (s, 1H), 1.49 (s, 9H). MS (+ESI) m/z: 520.1.

Step I—Synthesis of Compound 41 and 42

To a solution of Int-11h (100 mg, 0.193 mmol) in dimethylsulfoxide (5mL) were added (2,4-difluorophenyl)methanamine (138 mg, 0.965 mmol),N,N-diisopropylethylamine (0.337 mL, 1.929 mmol) and Pd(Ph₃P)₄ (111 mg,0.096 mmol). The mixture was stirred at 90° C. for 7 hours under carbonmonoxide (1 atm), cooled to rt and filtered. The filtrate was dilutedwith water (10 mL) and extracted with ethyl acetate (10 mL×3). Theorganic layer was washed with 1 M HCl (10 mL) and brine (10 mL), driedover anhydrous Na₂SO₄, filtered and the filtrate was concentrated. Theresidue was concentrated and purified by preparative TLC on silica gel(50% ethyl acetate in dichloromethane) to give the product as theracemate. MS (+ESI) m/z: 609.3.

Resolution to the enantiomers was accomplished with SFC (AD, 3×25 cm,55% ethanol with 0.1% ammonium hydroxide in SC—CO₂, 80 mL/min, 220 nm)to give compound 41 (enantiomer A) and compound 42 (enantiomer B).

Compound 41: ¹H NMR (400 MHz, CDCl₃) δ 10.42 (s, 1H), 8.50 (d, J=18.0Hz, 1H), 7.61 (d, J=7.2 Hz, 2H), 7.26-7.45 (m, 4H), 6.73-6.87 (m, 2H),5.28 (s, 2H), 4.63 (d, J=5.6 Hz, 2H), 3.46-3.68 (m, 6H), 3.14 (s, 3H),2.44-2.54 (m, 1H), 2.19 (s, 1H), 1.48 (s, 9H)

Compound 42: ¹H NMR (400 MHz, CDCl₃) δ 10.41 (s, 1H), 8.48 (d, J=20.0Hz, 1H), 7.60 (d, J=7.2 Hz, 2H), 7.25-7.42 (m, 4H), 6.75-6.86 (m, 2H),5.26 (s, 2H), 4.62 (d, J=5.6 Hz, 2H), 3.49-3.82 (m, 6H), 3.12 (s, 3H),2.41-2.51 (m, 1H), 2.17 (s, 1H), 1.48 (s, 9H)

Example 12 Preparation of Intermediate Compound 43

To a solution of compound 41 (enantiomer A) (20 mg, 0.033 mmol) in ethylacetate (1.8 mL) was added a solution of HCl in ethyl acetate (4 M, 0.6mL) at 0° C. The mixture was stirred at 25° C. for 1.5 h and thenconcentrated. The residue was purified by preparative TLC on silica gel(7% methanol in dichloromethane) to afford compound 43. ¹H NMR (400 MHz,CDCl₃) δ 10.52 (s, 1H), 8.77 (s, 1H), 7.55-7.68 (m, 1H), 7.62 (d, J=7.2Hz, 2H), 7.27-7.44 (m, 4H), 6.74-6.88 (m, 2H), 5.29 (s, 2H), 4.63 (d,J=5.6 Hz, 2H), 3.46-3.63 (m, 3H), 3.37 (d, J=12.0 Hz, 2H), 3.09-3.26 (m,5H), 2.30 (dd, J=6.8, 13.6 Hz, 1H), 2.08-2.17 (m, 3H). MS (+ESI) m/z:509.3.

Example 13 Preparation of Intermediate Compound 44

To a solution of compound 42 (enantiomer B) (25 mg, 0.041 mmol) in ethylacetate (0.9 mL) was added a solution of HCl in ethyl acetate (4 M, 0.3mL) at 0° C. The mixture was stirred at 25° C. for 1.5 h and thenconcentrated. The residue was purified by preparative TLC on silica gel(7% methanol in dichloromethane) to afford compound 44. ¹H NMR (400 MHz,CDCl₃) δ 10.51 (brs, 1H), 8.76 (s, 1H), 7.62 (d, J=7.2 Hz, 2H),7.27-7.43 (m, 4H), 6.76-6.85 (m, 2H), 5.24-5.31 (m, 2H), 4.62 (d, J=5.6Hz, 2H), 3.46-3.64 (m, 2H), 3.32-3.41 (m, 2H), 3.10-3.25 (m, 5H), 2.29(td, J=6.8, 13.6 Hz, 1H), 2.09-2.19 (m, 1H), 2.00-2.08 (m, 1H). MS(+ESI) m/z: 509.2.

Example 14 Preparation of Compound 45

Step A—Synthesis of Intermediate Compound Int-14a

To a solution of compound 43 (15 mg, 0.029 mmol) in dichloromethane (0.5mL) was added triethylamine (0.012 mL, 0.088 mmol) and acetyl chloride(2.78 mg, 0.035 mmol) at 0° C. The mixture was stirred at 25° C. for 5minutes, quenched with methanol and concentrated. The residue waspurified by preparative TLC on silica gel (7% methanol indichloromethane) to afford Int-14a. ¹H NMR (400 MHz, CDCl₃) δ10.31-10.45 (m, 1H), 8.38-8.54 (m, 1H), 7.61 (d, J=7.2 Hz, 2H),7.29-7.42 (m, 4H), 6.75-6.88 (m, 2H), 5.24-5.33 (m, 2H), 4.63 (d, J=5.6Hz, 2H), 4.06 (d, J=13.6 Hz, 1H), 3.53-3.82 (m, 5H), 3.12-3.20 (m, 3H),2.55-2.63 (m, 1H), 2.33 (td, J=9.2, 14.09 Hz, 1H), 2.09-2.19 (m, 3H). MS(+ESI) m/z: 551.2.

Step B—Synthesis of Compound 45

A solution of Int-14a (10 mg, 0.018 mmol) and LiCl (30.8 mg, 0.727 mmol)in N,N-dimethylformamide (1 mL) was stirred at 80° C. for 1.5 hours. Themixture was cooled to rt and concentrated. The residue was purified byRP-HPLC to afford compound 45. ¹H NMR (400 MHz, CDCl₃) δ 12.80 (brs,1H), 10.31-10.42 (m, 1H), 8.35-8.48 (m, 1H), 7.35 (d, J=7.2 Hz, 1H),6.75-6.87 (m, 2H), 4.63 (d, J=4.4 Hz, 2H), 4.08 (d, J=10.4 Hz, 1H), 3.77(s, 5H), 3.23 (s, 3H), 2.65 (s, 1H), 2.25 (s, 1H), 2.07-2.17 (m, 3H). MS(+ESI) m/z: 461.2.

Example 15 Preparation of Compound 46

Compound 46 was prepared from compound 44 in a similar manner to Example14. ¹H NMR (400 MHz, CDCl₃) δ 12.76 (brs, 1H), 10.28-10.40 (m, 1H),8.34-8.47 (m, 1H), 7.31-7.40 (m, 1H), 6.75-6.88 (m, 2H), 4.62 (d, J=5.2Hz, 2H), 4.07 (d, J=13.6 Hz, 1H), 3.68-3.87 (m, 5H), 3.22 (s, 3H), 2.65(d, J=7.2 Hz, 1H), 2.32-2.40 (m, 1H), 2.06-2.15 (m, 3H). MS (+ESI) m/z:461.2.

Example 16 Preparation of Compound 47

Step A—Synthesis of Intermediate Compound Int-16a

To a solution of compound 43 (22 mg, 0.043 mmol) in dichloromethane (4mL) was added triethylamine (0.018 mL, 0.130 mmol) and methanesulfonylchloride (5.06 μL, 0.065 mmol) at 0° C. The mixture was stirred at 0° C.for 1 h, quenched with water (10 mL) and extracted with dichloromethane(10 mL×3). The organic phase was dried over anhydrous Na₂SO₄, filteredand the filtrate was concentrated. The residue was purified bypreparative TLC (50% ethyl acetate in dichloromethane) to affordInt-16a. ¹H NMR (400 MHz, CDCl₃) δ 10.39 (t, J=5.2 Hz, 1H), 8.51 (s,1H), 7.59 (d, J=7.2 Hz, 2H), 7.28-7.40 (m, 4H), 6.77-6.87 (m, 2H), 5.23(s, 2H), 4.62 (d, J=5.6 Hz, 2H), 3.73-3.82 (m, 2H), 3.49-3.63 (m, 4H),3.46-3.47 (m, 3H), 3.12 (s, 3H), 2.44-2.52 (m, 1H), 2.20-2.29 (m, 1H).MS (+ESI) m/z: 587.2.

Step B—Synthesis of Compound 47

A solution of compound Int-16a (10 mg, 0.017 mmol) and LiCl (28.9 mg,0.682 mmol) in N,N-dimethylformamide (1 mL) was stirred at 80° C. for1.5 hours under nitrogen. The mixture was concentrated and the residuewas purified by RP-HPLC to afford compound 47. ¹H NMR (400 5 MHz, CDCl₃)δ 10.44 (brs, 1H), 8.53 (s, 1H), 7.31-7.37 (m, 1H), 6.76-6.86 (m, 2H),4.63 (d, J=5.2 Hz, 2H), 3.90 (d, J=12.0 Hz, 2H), 3.69-3.79 (m, 2H), 3.53(d, J=11.2 Hz, 2H), 3.23 (s, 3H), 3.03 (s, 3H), 2.65 (s, 1H), 2.27-2.35(m, 1H). MS (+ESI) m/z: 497.1.

Example 17 Preparation of Compound 48

Compound 48 was prepared from compound 44 in a similar manner to Example16. ¹H NMR (400 MHz, CDCl₃) δ 10.39 (brs, 1H), 8.52 (s, 1H), 7.31-7.38(m, 1H), 6.77-6.85 (m, 2H), 4.63 (d, J=5.2 Hz, 2H), 3.90 (d, J=12.0 Hz,2H), 3.69-3.79 (m, 2H), 3.53 (d, J=11.6 Hz, 2H), 3.23 (s, 3H), 3.03 (s,3H), 2.64 (s, 1H), 2.27-2.34 (m, 1H). MS (+ESI) m/z: 497.1.

Example 18 Preparation of Compound 49

Step A—Synthesis of Intermediate compound Int-18a

To a solution of compound 43 (20 mg, 0.039 mmol) inN,N-dimethylformamide (0.5 mL) was added K₂CO₃ (16.31 mg, 0.118 mmol)and MeI (3.69 μL, 0.059 mmol) at 0° C. under nitrogen. The mixture wasstirred at 25° C. for 1.5 h and then extracted with ethyl acetate (10mL) and water (3×10 mL). The combined organics were washed with brine,dried over anhydrous Na₂SO₄, filtered and the filtrate was concentrated.The residue was purified by preparative TLC on silica gel (50% ethylacetate in dichloromethane) to afford compound Int-18a. ¹H NMR (400 MHz,CDCl₃) δ 10.54 (brs, 1H), 8.94 (brs, 1H), 7.62 (d, J=7.2 Hz, 2H),7.27-7.43 (m, 4H), 6.76-6.87 (m, 2H), 5.22-5.35 (m, 2H), 4.64 (d, J=5.6Hz, 2H), 3.60 (d, J=13.6 Hz, 1H), 3.37-3.49 (m, 1H), 3.04-3.22 (m, 5H),2.52 (d, J=9.2 Hz, 2H), 2.33-2.45 (m, 3H), 2.23 (d, J=8.4 Hz, 2H). MS(+ESI) m/z: 523.2.

Step B—Synthesis of Compound 49

A solution of compound Int-18a (10 mg, 0.019 mmol) and LiCl (32.5 mg,0.765 mmol) in N,N-dimethylformamide (1 mL) was stirred at 80° C. for1.5 hours, cooled to rt and concentrated. The residue was purified byRP-HPLC to afford compound 49. ¹H NMR (400 MHz, CD₃OD) δ 8.56 (s, 1H),7.39-7.46 (m, 1H), 6.88-7.01 (m, 2H), 4.63 (s, 2H), 3.96 (d, J=13.6 Hz,1H), 3.73-3.84 (m, 2H), 3.60 (q, J=6.8 Hz, 3H), 3.20 (s, 3H), 2.93 (s,3H), 2.72 (s, 1H), 2.61 (s, 1H). MS (+ESI) m/z: 433.1.

Example 19 Preparation of Compound 50

Compound 50 was prepared from compound 44 in a similar manner to Example18. ¹H NMR (400 MHz, CD₃OD) δ 8.54 (s, 1H), 7.37-7.46 (m, 1H), 6.87-7.01(m, 2H), 4.62 (s, 2H), 3.96 (d, J=13.6 Hz, 1H), 3.72-3.84 (m, 2H), 3.58(q, J=7.2 Hz, 3H), 3.20 (s, 3H), 2.93 (s, 3H), 2.72 (s, 1H), 2.61 (s,1H). MS (+ESI) m/z: 433.2.

Example 20 Preparation of Compound 51

To a solution of compound 41 (25 mg, 0.041 mmol) in dichloromethane (1mL) was added trifluoroacetic acid (0.2 mL) at 0° C. The mixture wasstirred at 25° C. for 40 minutes and then concentrated. The residue waspurified by RP-HPLC to afford compound 51. ¹H NMR (400 MHz, CD₃OD) δ8.41 (s, 1H), 7.37-7.47 (m, 1H), 6.87-6.99 (m, 2H), 4.55-4.67 (m, 2H),3.67-4.02 (m, 6H), 3.19 (s, 3H), 2.77-2.86 (m, 1H), 2.51-2.61 (m, 1H).MS (+ESI) m/z: 419.1.

Example 21 Preparation of Compound 52

Compound 52 was prepared from compound 42 in a similar manner to Example20. ¹H NMR (400 MHz, CD₃OD) δ 8.42 (s, 1H), 7.39-7.48 (m, 1H), 6.88-7.01(m, 2H), 4.62 (s, 2H), 3.69-4.03 (m, 6H), 3.20 (s, 3H), 2.78-2.86 (m,1H), 2.53-2.62 (m, 1H). MS (+ESI) m/z: 419.0.

Example 22 Preparation of Compound 53

Step A—Synthesis of Intermediate Compound Int-22a

A mixture of (f)-Int-5e (210 mg, 0.518 mmol) and finely-ground potassiumcarbonate (286 mg, 2.073 mmol) in N,N-dimethylacetamide (10 mL) waspurging with nitrogen, stirred at rt for 20 min, treated withfinely-ground cesium carbonate (507 mg, 1.555 mmol) and purging withnitrogen. The mixture was stirred at rt for 20 min before diethyl2-bromoethylphosphonate (635 mg, 2.59 mmol) was added. The mixture wasthen heated under microwave irradiation at 120° C. for 2 h. Aftercooling to rt, the solids were removed by filtration and the filtratewas concentrated. The residue was purified by column chromatography onsilica gel (50 to 95% acetone in hexane) to provide compound Int-22a. MS(+ESI) m/z: 569.0, 571.0

Step B—Synthesis of Intermediate Compound Int-22b

A mixture of Int-22a (115 mg, 0.202 mmol), Pd(OAc)₂ (2.3 mg, 0.010mmol), bis(2-diphenylphophinophenyl)ether (6.5 mg, 0.012 mmol) andacetonitrile (3.5 mL) in an Endeavor® reaction tube was stirred at rtfor 10 min and then treated with triethylamine (0.056 mL, 0.404 mmol)and 2,4-difluorobenzylamine (0.029 mL, 0.242 mmol). The mixture wasstirred at 80° C. under carbon monoxide (40 psi) for 6 hours,concentrated. The residue was purified by column chromatography onsilica gel (5 to 10% methanol in dichloromethane) to provide compoundInt-22b. MS (+ESI) m/z: 660.2

Step C—Synthesis of Compound 32

A solution of Int-22b (60 mg, 0.091 mmol) in dichloromethane (3 mL) wascooled to 0° C. and treated with bromotrimethylsilane (0.071 mL, 0.546mmol). The mixture was slowly warmed to rt and stirred over 2 h, treatedwith additional bromotrimethylsilane (0.071 mL, 0.546 mmol), stirred atrt for 18 h and concentrated. The residue was triturated with 50% ethylacetate in hexane (5 mL) and the solids were collected by filtration andwashed with 50% ethyl acetate in hexane (2×10 mL) to provide compound32. MS (+ESI) m/z: 514.2

Step D—Synthesis of Compound 53

A mixture of 32 (35 mg, 0.068 mmol), (S)-isopropyl 2-aminopropanoatehydrochloride (20.57 mg, 0.123 mmol) and phenol (25.7 mg, 0.273 mmol)were weighed into a flask and purged with nitrogen. Pyridine (2 mL) wasadded and the reaction was warmed to 60° C. with stirring. A solution of2,2′-dipyridyl disulfide (90 mg, 0.409 mmol), triphenylphosphine (107mg, 0.409 mmol) and triethylamine (0.114 ml, 0.818 mmol) in pyridine (4mL) was added. The reaction was stirred at 60° C. under nitrogen for 18h, cooled to rt, and concentrated. The residue was purified purified bycolumn chromatography on silica gel (10 to 15% methanol indichloromethane). Further purification by RP-HPLC (10 to 33%acetonitrile in water with 0.1% NH₄HCO₃ modifier) to provide compound 53as a mixture of four stereoisomers. ³¹P NMR (500 MHz, CD₃CN) δ 28.02,27.98, 27.39, 27.34. MS (+ESI) m/z: 703.2

Example 23 Preparation of Compound 54

The single enantiomer of Int-22c (enantiomer A) was prepared fromInt-5e-1 (enantiomer A) according to the procedure outlined in Example22. To a solution of Int-22c (enantiomer A) (80 mg, 0.156 mmol) inN,N-dimethylformamide (2 mL) at rt was added triethylamine (0.174 ml,1.247 mmol) and chloromethyl isopropyl carbonate (83 mg, 0.545 mmol).The mixture was heated at 60° C. for 18 h, cooled to rt and partitionedbetween dichloromethane (5 mL) and water (5 mL). The organic phase waswashed with water (3×10 mL), dried with anhydrous Na₂SO₄ andconcentrated. The residue was purified three times by columnchromatography on silica gel (7% methanol in dichloromethane) to providecompound 54. ¹H NMR (500 MHz, CD₃CN) δ 12.79 (s, 1H), 10.39 (t, J=5.9Hz, 1H), 8.45 (s, 1H), 7.41 (dd, J=8.4, 15.0 Hz, 1H), 6.91-6.97 (m, 2H),5.56-5.65 (m, 4H), 4.85-4.90 (m, 2H), 4.57 (d, J=6.0 Hz, 2H), 4.27 (d,J=11.1 Hz, 1H), 4.06 (dd, J=1.6, 3.2 Hz, 1H), 3.92-3.97 (m, 1H),3.76-3.85 (m, 5H), 2.23-2.42 (m, 4H), 2.16 (s, 12H); ³¹P NMR (500 MHz,CD₃CN) δ 28.02. MS (+ESI) m/z: 746.2

Compounds 55 and 56 were prepared from Int-5e-1 (enantiomer A) accordingto the procedure outlined in Example 22.

Compound Exact Mass Number Structure Stereochemistry [M + H]⁺ 55

enantiomer A Calc'd 513.1, found 514.2 56

enantiomer A epimers at P, mixture of 2 stereoisomers Calc'd 702.2,found 703.2

Compounds 57 and 58 were prepared from Int-5e-2 (enantiomer B) accordingto the procedure outlined in Examples 22 and 23.

Compound Exact Mass Number Structure Stereochemistry [M + H]⁺ 57

enantiomer B Calc'd 513.1, found 514.0 58

enantiomer B Calc'd 745.2, found 746.0

Example 24 Assay for Inhibition of HIV Replication

MT4-GFP cells (250,000 cells/ml) were bulk-infected with HIV-1 (NL4-3strain) at low multiplicity of infection (MOI) in RPMI+10% FBS for 24hours. Cells were then washed once in RPMI+10% FBS and resuspendedRPMI+10% or 50% normal human serum (NHS). Test compounds wereserial-diluted in DMSO on ECHO. The infected MT4-GFP cells were added toa 384-well poly-D-lysine coated black plate with clear bottom in whichthe diluted test compounds were placed. The cells were seeded at 8,000cells per well and the final DMSO concentration was 0.4%. The infectedcells (Green GFP cells) were quantified at both 24 and 48 hours postincubation using Acumen eX3. Viral reproductive ratio (R₀) wasdetermined using the number of infected cells at 48 hours divided by thenumber of infected cells at 24 hours. Percent viral growth inhibitionwas calculated by [1−(R−R_(tripledrug))/(R_(DMSO)−R_(tripledrug))]*100.Compound potency IP or IC₅₀ was determined by a 4-parameter doseresponse curve analysis with data for selected compounds of the presentinvention presented in the table below.

VIKING IP₅₀ (nM) VIKING IP₅₀ (nM) Compound with 0% NHS with 100% NHS 1 41282 2 19 1514 3 3 292 4 2 334 5 4 >8400 6 6 646 7 6 113 8 2 260 9 2 81410 3 75 11 3 442 12 5 47 13 2 36 14 3 209 15 4 108 16 2 4529 17 2 >840018 3 >8400 19 2 3422 20 2 337 21 3 129 22 2 40 23 1 27 24 35 >8000 25 11729 26 1 1137 27 3 3661 28 2 2769 29 1 1145 30 1 417 31 17 232 32 293873 33 3 210 34 5 4916 35 1 88 36 3 114 37 3 663 38 7 235 39 2 291 40 4691 45 69 297 46 19 259 47 6 78 48 10 112 49 2 90 50 1 74 51 3 68 52 18210 53 4 160 54 5 1600 58 7 530

What is claimed is:
 1. A compound having the formula:

or a pharmaceutically acceptable salt thereof, wherein: A is —NHC(O)—; Bis a 3 to 8-membered heterocycloalkyl, which can be optionallysubstituted with one or more groups, each independently selected fromR⁵; X is C₁-C₄ alkylene; R¹ is selected from H, C₁-C₆ alkyl, C₃-C₇cycloalkyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, —(C₁-C₄alkylene)-O—(C₁-C₆ alkyl), —(C₁-C₄ alkylene)-S—(C₁-C₆ alkyl), —(C₁-C₄alkylene)-SO₂—(C₁-C₆ alkyl), —N(C₁-C₆ alkyl)₂, —(C₁-C₄ alkylene)-N(C₁-C₆alkyl)₂, —(C₁-C₄ alkylene)-P(O)(—O—C₁-C₆ alkyl)₂, —(C₁-C₄alkylene)-P(O)(OH)₂, phenyl, 3 to 8-membered monocyclic heterocycloalkyland 5- or 6-membered monocyclic heteroaryl; R² represents up to 3optional substitutents, each independently selected from halo, C₁-C₆alkyl, —O—(C₁-C₆ alkyl) and C₁-C₆ haloalkyl; each occurrence of R³ isindependently selected from H, C₁-C₆ alkyl, —OH, —O —(C₁-C₆ alkyl),C₁-C₆ haloalkyl, C₃-C₇ cycloalkyl, —S—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆alkyl) and —N(C₁-C₆ alkyl)₂; R⁴ is selected from H, C₁-C₆ alkyl, C₃-C₇cycloalkyl, —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl) and C₁-C₆ haloalkyl; eachoccurrence of R⁵ is independently selected from halo, C₁-C₆ alkyl, C₁-C₆haloalkyl, 3 to 8-membered monocyclic heterocycloalkyl, 6 to 10-memberedbicyclic heterocycloalkyl, —O—(C₁-C₆ alkyl), —O—(C₆-C₁₀ aryl), —O—(C₁-C₆alkylene)-O—(C₁-C₆ alkyl), —O—(C₁-C₆ haloalkyl), —O—(C₁-C₆alkylene)-O—(C₁-C₆ alkylene)-O—(C₁-C₆ alkyl), —NH₂, —NH(C₁-C₆ alkyl),—N(C₁-C₆ alkyl)₂, —S(O)₂(C₁-C₆ alkyl), —NHS(O)₂-(C₁-C₆ alkyl),—S(O)₂NH—(C₁-C₆ alkyl), —OC(O)—(C₁-C₆ haloalkyl), —(C₁-C₆alkylene)_(p)—C(O)O—(C₁-C₆ alkyl), —(C₁-C₆ alkylene)_(p)—C(O)—(C₁-C₆alkyl), —(C₁-C₆ alkylene)_(p)—C(O)N(R⁶)₂, C₁-C₆ hydroxyalkyl,—P(O)(OR⁸)₂, and —CN; each occurrence of R⁶ is independently selectedfrom H, C₁-C₆ alkyl, C₃-C₇ cycloalkyl, C₁-C₆ haloalkyl and —(C₁-C₆alkylene)_(p)-R⁷; each occurrence of R⁷ is independently selected fromH, C₁-C₆ alkyl, —O—(C₁-C₆ alkyl), C₃-C₇ cycloalkyl, 5- or 6-memberedmonocyclic heteroaryl and 3 to 8-membered monocyclic heterocycloalkyl;each occurrence of R⁸ is independently selected from H and C₁-C₆ alkyl;and each occurrence of p is independently 0 or
 1. 2. The compound ofclaim 1, wherein X is —CH₂—, or a pharmaceutically acceptable saltthereof.
 3. The compound of claim 1, having the formula:

or a pharmaceutically acceptable salt thereof, wherein: A is: —NHC(O)—;B is 4 to 7-membered monocyclic heterocycloalkyl; R¹ is selected fromC₁-C₆ alkyl, C₁-C₆ hydroxyalkyl and —(C₁-C₄ alkylene)-O—(C₁-C₆ alkyl);R² represents up to 2 optional substituents, each independently selectedfrom halo; and each occurrence of R³ is independently H or C₁-C₆ alkoxy.4. The compound of claim 1, wherein B is selected from:

or a pharmaceutically acceptable salt thereof.
 5. The compound of claim1, wherein R² represents up to 3 substituent groups, each independentlyselected from F and Cl, or a pharmaceutically acceptable salt thereof.6. The compound of claim 5, wherein R² and the phenyl group to which R²is attached is:

or a pharmaceutically acceptable salt thereof.
 7. The compound of claim1, wherein ¹ is selected from methyl, ethyl, —CH₂OCH₃, —CH₂CH₂OCH₃,—CH₂CH₂CH₂OCH₃ and —CH₂CH₂OCH₂CH₃, or a pharmaceutically acceptable saltthereof.
 8. The compound of claim 1, wherein one occurrence of R³ is Hand the other occurrence of R³ is H or methoxy, or a pharmaceuticallyacceptable salt thereof.
 9. A compound selected from

or a pharmaceutically acceptable salt thereof.
 10. A pharmaceuticalcomposition comprising an effective amount of a compound according toclaim 1, or a pharmaceutically acceptable salt thereof, and apharmaceutically acceptable carrier.
 11. A method for the treatment ofinfection by HIV or for the treatment of AIDS in a subject in needthereof, which comprises administering to the subject an effectiveamount of the compound according to claim 1, or a pharmaceuticallyacceptable salt thereof.
 12. The pharmaceutical composition of claim 10,further comprising one or more additional therapeutic agents selectedfrom raltegravir, lamivudine, abacavir, ritonavir, dolutegravir,arunavir, atazanavir, emtricitabine, tenofovir, elvitegravir,rilpivirine and lopinavir.
 13. The method of claim 11, furthercomprising administering to the subject one or more additionaltherapeutic agents selected from raltegravir, abacavir, lamivudine,ritonavir and lopinavir, wherein the amounts administered of thecompound of claim 1 and the one or more additional therapeutic agents,are together effective to treat infection by HIV or to treat AIDS.